CN102933658A - Local delivery of drugs from self assembled coatings - Google Patents

Local delivery of drugs from self assembled coatings Download PDF

Info

Publication number
CN102933658A
CN102933658A CN2010800640811A CN201080064081A CN102933658A CN 102933658 A CN102933658 A CN 102933658A CN 2010800640811 A CN2010800640811 A CN 2010800640811A CN 201080064081 A CN201080064081 A CN 201080064081A CN 102933658 A CN102933658 A CN 102933658A
Authority
CN
China
Prior art keywords
self
medical supply
biologically active
class
active agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN2010800640811A
Other languages
Chinese (zh)
Inventor
露茜塔·埃斯范德
J·保罗·桑泰尔
西尔维娅·贾亚迪
贝尔纳黛特·伊拉干
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
INTERFACE BIOLOG Inc
Interface Biologics Inc
Original Assignee
INTERFACE BIOLOG Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by INTERFACE BIOLOG Inc filed Critical INTERFACE BIOLOG Inc
Publication of CN102933658A publication Critical patent/CN102933658A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6957—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a device or a kit, e.g. stents or microdevices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/002—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from unsaturated compounds
    • C08G65/005—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from unsaturated compounds containing halogens
    • C08G65/007—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from unsaturated compounds containing halogens containing fluorine
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/1045—Balloon catheters with special features or adapted for special applications for treating bifurcations, e.g. balloons in y-configuration, separate balloons or special features of the catheter for treating bifurcations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • A61M2025/1043—Balloon catheters with special features or adapted for special applications
    • A61M2025/105—Balloon catheters with special features or adapted for special applications having a balloon suitable for drug delivery, e.g. by using holes for delivery, drug coating or membranes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L2203/00—Applications
    • C08L2203/02—Applications for biomedical use

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Polymers & Plastics (AREA)
  • Molecular Biology (AREA)
  • Vascular Medicine (AREA)
  • Surgery (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Anesthesiology (AREA)
  • Biophysics (AREA)
  • Child & Adolescent Psychology (AREA)
  • Transplantation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to oligofluorinated coatings and their use in drag delivery The oligofluorinated coatings are compositions comprising formula (XVII). These coatings are used in a method of delivering a biologically active agent to a tissue surface in a mammalian tissue This method occurs by contacting the surface with the coating including an oligofluorinated oligomer and a biologically active agent wherein the coating resides on the tissue surface and release the biologically active agent to the tissue surface.

Description

From self-assembled coating local delivery medicine
Quoting of related application
The application requires the rights and interests of the U.S. Provisional Application submitted on December 18th, 2009 number 61/287,862, by reference it is combined in this.
Technical field
The present invention relates to self-assembled coating and preparation that fluorinated oligomeric thing and therapeutical agent are agglomerated into, and their purposes in drug delivery.
Background technology
Use implantable devices for example bracket for eluting medicament (DES) realized that topical therapeutic sends, comprise the control hyperblastosis or grow into treatment in the vessel open passage.Yet these equipment are incomplete and may cause frequently side effect.The existence of residual foreign matter may cause the damaging inflammatory reaction and bring out coalescent.Can come the surface of modification implantable devices to be used for improving biocompatibility and thrombus tolerance and give the characteristic different from this equipment and materials with multiple technologies, for example, anti-infectivity (that is, by sending biologically active agent), radiation impermeability, electroconductibility etc.In the DES field, these technology have obtained limited success.
Temporary medical supply, the equipment that namely stops in vivo very short time durations (insert and take out) can also be used as topical therapeutic delivery vehicle (carrier).Compare with permanent implantable medical supply, it can be more favourable using temporary medical supply (for example, balloon catheter, seal wire, syringe needle or probe), because there is not long-term biocompatibility issues.
Because the problem that is associated with DES, the design of using medicament elution air bag (DEB) conduit that anti-restenosis medicaments (for example taxol) is delivered to the arteriopathy position partly has been regarded as providing the chance of replacement therapy now, and this replacement therapy has been avoided the many misgivings relevant with DES.When inflation, when (tube chamber, when lumen) wall contacted limiting time, this DEB conduit is the medicine of delivery treatments amount effectively with lumen.
Since two thousand six DEB conduit approach has become the theme of several clinical trials.Yet, because for the inherent limitations of the carrier molecule of these medicines, the result of many these tests, comprise by same companies with the material of slightly again preparation repeat several, obtained limited success.General strategy is the medicinal breast formed material coating balloon catheter (referring to U.S. Patent Publication No. 20060020243) of using the dying agent of determining or having definite adjusting history.The result (for example is being lower than optimum performance aspect the reservation to air bag between delivery period in tube chamber, even before arriving destination organization the medicine of possible loss 90%, some of them absorb in the air bag, and＜6% be transferred to illing tissue) (referring to the people such as Axel De Labriolle, Catheterization and Cardiovascular Interventions73:643 (2009)).
These result's proofs are for solving the synthesis module approach existence needs that medicine keeps restriction in the local organization by medicine is transferred to efficiently and preferably.In order to address these limitations, carrier molecule need to be designed to when arriving the air bag of target site, to have low blood activation by reducing the carrier system local delivery.
Summary of the invention
Method of the present invention and composition feature are oligomer (oligomer) compounds (for example, the coating of fluoridizing and preparation) of branch, and their purposes aspect drug delivery.
In first aspect, feature of the present invention is a kind of composition of following formula:
Figure BDA00002022515600021
Wherein
M and n both 0, or m and n both 1;
Each A and A 2It is the trifunctional monomer with molecular weight between the 50-3500Da;
Each L and L AJoint independently;
Each R X1A, R X1B, R X2A, and R X2BTo have 200-3 independently, the insoluble segment of the water of molecular weight between the 500Da (water-fast section, water insoluble segment); And
R Y1To have 200-3, organic segment of the not halogenation of molecular weight between the 500Da; And
As m and n both 1 time, each R Z1And R Z2To have 50-3 independently, the insoluble segment of difunctionality water of molecular weight between the 500Da, or
As m and n both 0 time, each R Z1And R Z2To have 200-3 independently, the insoluble segment of the water of molecular weight between the 500Da.
In some embodiments, said composition has following formula
Figure BDA00002022515600031
Wherein
A is the trifunctional monomer with molecular weight between the 50-3500Da; Each L is joint independently;
R Z1And R Z2To have 200-3 independently of one another, the insoluble segment of the water of molecular weight between the 500Da (for example, Organohalogen compounds segment); And
R Y1To have 100-3, organic segment of the not halogenation of molecular weight between the 500Da.
In some embodiments, A is the trifunctional monomer with molecular weight between the 50-1000Da; Each L is joint independently; R Z1And R Z2Be the insoluble segment of water independently of one another, for example have 200-3, the Organohalogen compounds segment of molecular weight between the 500Da; And R Y1To have 100-3, organic segment of the not halogenation of molecular weight between the 500Da.
In other embodiments, said composition illustrates by following formula (XV-B):
In other embodiments, said composition has following formula
Figure BDA00002022515600032
Wherein
Each A and A 2It is the trifunctional monomer with molecular weight between the 50-3500Da; Each L and L AJoint independently; Each R X1A, R X1B, R X2A, and R X2BTo have 200-3 independently of one another, the insoluble segment of the water of molecular weight between the 500Da; And R Y1To have 100-3, organic segment of the not halogenation of molecular weight between the 500Da, and each R Z1To have 100-3 independently, the insoluble segment of difunctionality water of molecular weight between the 500Da.In some embodiments, R Z1It is the glycol of fluoridizing.Those skilled in the art should be understood that can increase these R-sample branches is used for further producing branch.Similarly, one skilled in the art will appreciate that if desired R Y1Part can also have the segment of branch.In some embodiments, A comprises trivalent alcohol.
In other embodiments, A comprises glycerine, TriMethylolPropane(TMP) (TMP), trimethylolethane (TME), trimesic acid (TMA) or three (hydroxyethyl) chlorinated isocyanurates (THEIC).
In any one of following formula, R Y1Can be branch or branch not.
In certain embodiments, R Y1The polyoxyethylene glycol, the zwitter-ion that are straight or branched (comprise the zwitterionics part, for example, alkyl betaine class, for example alkyl aminopropyl trimethyl-glycine, sultaine and alkylsulphonic acid trimethyl-glycine (alkyl sultaines), alkyl oxide hydroxypropyl sulphonic acid betaine (alkyl ether hydroxyl propyl sultaines) and alkyl aminopropyl hydroxyl sulfoacid trimethyl-glycine (alkylamidopropylhydroxy sultaines)) or polyvinylpyrrolidone.
In other embodiments, R Z1And R Z2Poly-fluorine organic group, polysiloxane group or polyolefine group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BPoly-fluorine organic group, polysiloxane group or polyolefine group independently of one another.
In another other embodiments, R Z1And R Z2The silicone group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BThe silicone group independently of one another.
In other embodiments, said composition is by following formula explanation,
Figure BDA00002022515600041
F wherein TIt is poly-fluorine organic group; L is joint; X 1H, CH 3, or CH 2CH 3
X 2H, CH 3, or CH 2CH 3And n is from 5 to 50 integer.
In any one of embodiment described herein, this joint is that through type (XVI) illustrates:
G 1-(Z 1) o-(Y 1) u-(Z 2) s-(R 10)-(Z 3) t-(Y 2) v-(Z 4) pG 2 （XVI）
Wherein
G 1It is a key between described poly-fluorine organic group and described joint;
G 2It is a key between described joint and Sauerstoffatom;
Z 1, Z 2, Z 3, and Z 4To be selected from O, S and NR independently of one another 11
R 11Hydrogen or C 1-10Alkyl group;
Y 1And Y 2Be selected from independently of one another carbonyl, thiocarbonyl, alkylsulfonyl or phosphoryl;
O, p, s, t, u and v are 0 or 1 independently of one another; And
R 10To replace or unsubstituted C 1-10Assorted alkyl, the C of alkyl, 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems of aryl, 3 to 10 atoms ,-(CH 2CH 2O) qCH 2CH 2-wherein q is 1 to 10 integer, or with G 1-(Z 1) o-(Y 1) u-(Z 2) s-be connected to-(Z 3) t-(Y 2) v-(Z 4) p-G 2On chemical bond.
In some embodiments, this joint be covalent linkage or-(C=O)-group.
In some embodiments, said composition is that through type (XVII) illustrates:
Figure BDA00002022515600051
F wherein TIt is poly-fluorine organic group; L 2To replace or unsubstituted C 1-10Assorted alkyl, the C of alkyl, 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems of aryl, 3 to 10 atoms ,-(CH 2CH 2O) qCH 2CH 2-wherein q is 1 to 10 integer; X 1H, CH 3, or CH 2CH 3X 2H, CH 3, or CH 2CH 3And n is from 5 to 50 integer.
In some embodiments, this poly-fluorine organic group is to have 100-1, the poly-fluoroalkyl of molecular weight between the 500Da.
In other embodiments, this poly-fluorine organic group is to have general formula CF 3(CF 2) rCH 2CH 2-or CF 3(CF 2) s(CH 2CH 2O) χ-group, wherein r is the integer from 2-10, χ is the integer from 1-10, and s is the integer from 1-20.
In another other embodiments, this poly-fluorine organic group is to have general formula CH mF (3-m)(CF 2) rCH 2CH 2-or CH mF (3-m)(CF 2) s(CH 2CH 2O) χ-group, wherein m is 0,1,2 or 3; χ is the integer between 1-10; R is the integer between 2-20; And s is the integer between 1-10.
In certain embodiments, this poly-fluorine organic group is to be selected from (CF 3) (CF 2) 5CH 2CH 2O-, (CF 3) (CF 2) 7CH 2CH 2O-, (CF 3) (CF 2) 5CH 2CH 2O-, CHF 2(CF 2) 3CH 2O-and (CF 3) (CF 2) 2CH 2O-, 1H, 1H, 2H, 2H-perfluor-1-decanol, 1H, 1H, 2H, 2H-perfluor-1-octanol, 1H, 1H, 5H-perfluor-1-amylalcohol and 1H, 1H, perfluor-n-butyl alcohol and their mixture.
In some embodiments, said composition comprises following mixture: (i) any is (for example in the composition described herein, the oligomeric oligopolymer of fluoridizing (oligomerization is fluoridized oligomer) (for example, branch or straight chain the oligomeric oligopolymer of fluoridizing) or comprise branch's compound of the insoluble segment of water); And (ii) a kind of medicine.In some embodiments, this medicine is hydrophobic drug (for example, this medicine is to be selected from antiproliferative class and rapamycin Macrolide).In some embodiments, this hydrophobic drug is to be selected from following antiproliferative: methotrexate, trimetrexate, gemcitabine, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol, Docetaxel, daunorubicin, Dx, gengshengmeisu, idarubicin, bleomycin and tamoxifen.In other embodiments, this hydrophobic drug is the rapamycin macrolide that is selected from rapamycin, CCI-779, everolimus and ABT-578.In other embodiments, this hydrophobic drug is taxol.In some embodiments, (i): (ii) be the ratio that is in 20:1 to 1:20.
In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be the compound that has in the formula (I)-(VIII) any, from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, from 4kDa to 12KDa, from 6kDa to 15KDa, from 5kDa to 25KDa, from 3kDa to 20KDa or from the molecular-weight average of 10kDa to 50KDa.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).This oligomeric oligopolymer of fluoridizing can be the grafting oligopolymer of formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be the crosslinked polymkeric substance that has in the formula (X)-(XIV) any.In other embodiments, this coating comprises the branch's compound that comprises the insoluble segment of water (water insoluble section).This branch's compound can be have formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in any compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, from 3kDa to 12KDa, from 6kDa to 15KDa, from 5kDa to 25KDa, from 12kDa to 40KDa or from the molecular-weight average of 15kDa to 50KDa.
In each of said embodiment, said composition further comprises water.In some embodiments, said composition is aqueous dispersion (for example, single-phase or two-phase dispersion).
In other embodiments, said composition is solid dispersion.
In another other embodiments, said composition is suitable for systemic injection.
In some embodiments, said composition is the form that is in liquid, tablet, capsule, powder, injection or suppository.
In some embodiments, the solubleness of this hydrophobic drug (solvability) is increased.
Any of composition described herein can be used for any of method described herein or temporary medical supply.
On the other hand, feature of the present invention is by tissue surface in the mammalian tissues is contacted with self-assembled coating biologically active agent to be delivered to this surperficial method, this coating (for example comprises (i) a kind of oligomeric oligopolymer of fluoridizing, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water and (ii) a kind of biologically active agent, wherein after contact, be positioned on this tissue surface and with this biologically active agent at this self-assembled coating under the medical supply that does not have implantation and be discharged on this tissue surface.
In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be the compound that has in the formula (I)-(VIII) each, from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, from 4kDa to 12KDa, from 6kDa to 15KDa, from 5kDa to 25KDa, from 3kDa to 20KDa or from 10kDa to 50KDa) molecular-weight average.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).The graft copolymer that this oligomeric oligopolymer of fluoridizing can be formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be the cross-linked polymer that has in the formula (X)-(XIV) any.In other embodiments, this coating comprises the branched compound that comprises the insoluble segment of water.This comprise branch's compound of the insoluble segment of water can be have formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in any compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, from 3kDa to 12KDa, from 6kDa to 15KDa, from 5kDa to 25KDa, from 12kDa to 40KDa or from 15kDa to 50KDa) molecular-weight average.
Feature of the present invention still is delivered to biologically active agent the method for this tissue by tissue surface in the mammalian tissues is contacted with the temporary medical supply that is coated with self-assembled coating, this self-assembled coating (for example comprises (i) oligomeric oligopolymer of fluoridizing, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water and (ii) biologically active agent, wherein when contact, this temporary medical supply is discharged into this biologically active agent on this tissue surface.In certain embodiments, this temporary medical supply can destroy this self-assembled coating, and when destroying, biologically active agent is discharged on the tissue surface.For example, this temporary medical supply can be deformable temporary medical supply, and when being launched into deformed configuration, this plant machinery ground destroys this self-assembled coating and biologically active agent is discharged on the tissue surface.Alternately, thus can be configured energy source is directed on this self-assembled coating to this temporary medical supply destroys self-assembled coating in response to energy (for example, ultrasonic energy, heat energy, electromagnetic energy or vibrational energy).Can this self-assembled coating be applied on the surface of this temporary medical supply by deposition of solids, spraying, printing or dip-coating.For example, can self-assembled coating be applied on the surface of this equipment with two-step approach, at first with the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's compound of the insoluble segment of water applies this equipment, secondly apply with biologically active agent.In some embodiments, the oligomeric oligopolymer of fluoridizing of the self-assembled coating on this temporary medical supply forms a self-assembly layer.This coating can have the thickness of from 0.01 to 250 micron (for example, from 0.01 to 5 micron, 0.1 to 5 micron, 1 to 5 micron, 1 to 25 micron, 2 to 25 microns, 5 to 50 microns, 5 to 100 microns, 10 to 250 microns, 15 to 50 microns or 20 to 125 microns).In specific embodiments, can be with from 5% to 55%(w/w) biologically active agent be delivered to the biologically active agent of (for example, sending from 5% to 35%, 15% to 85%, 20% to 95%, 25% to 65%, 25% to 85%, 35% to 65%, 35% to 95%, 40% to 95% or 55% to 95%(w/w) the mammalian tissues from this temporary medical supply).In this tissue surface is in some embodiment in the blood vessel, this self-assembled coating applies the surface of temporary medical supply, and before being delivered on this tissue surface, keep from 25% to 85%(w/w at this medical supply) the biologically active agent of biologically active agent (for example, keep from 25% to 75%, 25% to 65%, 35% to 95%, 35% to 75%, 45% to 95%, 45% to 75%, 55% to 95% or from 55% to 75%(w/w)).In another other embodiments, this temporary medical supply folds on himself, and when this temporary medical supply is launched into the unfolding configuration from folding configuration from 25% to 85%(w/w) biologically active agent be retained on this medical supply the biologically active agent of (for example, kept from 25% to 75%, 25% to 65%, 35% to 95%, 35% to 75%, 45% to 95%, 45% to 75%, 55% to 95% or from 55% to 75%(w/w)).
In some embodiment aspect above-mentioned, this tissue surface is lumen system (luminal system) (for example, the blood vessel of mammalian tissues, vein grafts, synthetic graft, or the tube chamber in breathing, uropoiesis, reproduction, nerve or Digestive tract (lumen, lumen)).For example, this self-assembled coating can be applied on the surface of balloon catheter, be inserted in the lumen system of mammalian tissues, and be launched into expanded configuration and be used for biologically active agent is transferred on the tissue surface of this lumen system from the surface of this balloon catheter.
In aspect above-mentioned any one, the oligomeric oligopolymer of fluoridizing of this self-assembled coating (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or the branch's compound that comprises the insoluble segment of water can be can be resorbent or can not be resorbent.In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be any compound in the formula (I)-(VIII), from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, 4kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 3kDa to 20KDa or from 10kDa to 50KDa) molecular-weight average.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).The graft copolymer that this oligomeric oligopolymer of fluoridizing can be formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be any cross-linked polymer in the formula (X)-(XIV).In other embodiments, this coating comprises the branch's compound that comprises the insoluble segment of water.This branch's compound can be formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in any compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, 3kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 12kDa to 40KDa or 15kDa to 50KDa) molecular-weight average.
In some embodiment aspect above-mentioned, this self-assembled coating is by from 1kDa to 60kDa(for example having, from 1kDa to 40kDa, 2kDa to 60kDa, 2kDa to 40kDa, 3kDa to 60kDa, 3kDa to 40kDa, 5kDa to 60kDa, 5kDa to 40kDa, 10kDa to 60kDa or from 15kDa to 60kDa) component of molecular weight forms.
In another other embodiments aspect above-mentioned, this oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's compound of the insoluble segment of water from 1kDa to 30kDa(for example has, from 1kDa to 60kDa, 2kDa to 60kDa, 2kDa to 30kDa, 3kDa to 60kDa, 3kDa to 30kDa, 5kDa to 60kDa, 5kDa to 30kDa, 10kDa to 60kDa or from 10kDa to 30kDa) theoretical molecular.
In the specific embodiments aspect above-mentioned, this oligomeric oligopolymer of fluoridizing comprises a hard segment, a soft chain segment and poly-fluorine organic group, wherein this oligomeric oligopolymer of fluoridizing comprises from 5% to 80%(w/w) hard segment, from 10% to 90%(w/w) soft chain segment, and from 5% to 80%(w/w) poly-fluorine organic group.
In aspect above-mentioned each, this biologically active agent can distribute equably and spread all over self-assembled coating.In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be each compound in the formula (I)-(VIII), from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, 4kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 3kDa to 20KDa or from 10kDa to 50KDa) molecular-weight average.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).The graft copolymer that this oligomeric oligopolymer of fluoridizing can be formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be any cross-linked polymer in the formula (X)-(XIV).In other embodiments, this coating comprises the branch's compound that comprises the insoluble segment of water.This branch's compound can be formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in each compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, 3kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 12kDa to 40KDa or from 15kDa to 50KDa) molecular-weight average.
In aspect above-mentioned each, this self-assembled coating can comprise from 1% to 30%(w/w) fluorine atom of fluorine atom (for example from 2% to 30%, 3% to 30%, 4% to 30%, 5% to 30%, 2% to 10%, 3% to 15% or 4% to 20%(w/w)).
In aspect above-mentioned each, this self-assembled coating comprises from 0.1% to 50%(w/w) the biologically active agent of biologically active agent (for example, from 0.1% to 10%, 0.5% to 30%, 1% to 50%, 2% to 50%, 2% to 30%, 3% to 50%, 0.5% to 5%, 0.5% to 10%, 1% to 10%, 2% to 15%, 2% to 25%, 3% to 15% or 3% to 25%(w/w)).
In aspect above-mentioned each, this self-assembled coating from 20:1 to 1:20(for example can comprise, from 1:1 to 1:20,20:1 to 1:1,10:1 to 1:10,1:1 to 1:10,10:1 to 1:1,5:1 to 1:5,1:1 to 1:5 or 5:1 to 1:1) the oligomeric oligopolymer of fluoridizing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's Compound Phase of the insoluble segment of water is for the molar ratio of biologically active agent.In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be any compound in the formula (I)-(VIII), from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, 4kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 3kDa to 20KDa or from 10kDa to 50KDa) molecular-weight average.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).The graft copolymer that this oligomeric oligopolymer of fluoridizing can be formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be any cross-linking copolymer in the formula (X)-(XIV).In other embodiments, this coating comprises the branch's compound that comprises the insoluble segment of water.This branch's compound can be formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in any compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, 3kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 12kDa to 40KDa or from 15kDa to 50KDa) molecular-weight average.
In aspect above-mentioned each, this self-assembled coating can have 80 ° of C to 40 ° of C(of Cong – for example 20 ° of C to 40 ° of C of 60 ° C to 5 ° C, of 80 ° C to 5 ° C, of ， Cong – Cong – Cong –, 50 ° C to 20 ° C, Cong –, 40 ° C to 30 ° C, Cong –, 30 ° C to 40 ° C, Cong –, 15 ° of C to 25 ° of C of Huo Cong –) glass transition temp.
In aspect above-mentioned each, this self-assembled coating from 1.0 to 200g(for example can have, from 1.0 to 100g, 1.0 to 50g, 2.0 to 200g, 2.0 to 100g, 2.0 to 50g, 1.0 to 25g, 2.0 to 25g, 3.0 to 75g, 3.0 to 50g, 3.0 to 25g or 1.0 to 20g) sorptive force (viscosity, tack).
In aspect above-mentioned each, this self-assembled coating can have from 0.04 to 130cps(for example, from 20 to 130cps, 50 to 130cps, 75 to 130cps, 0.04 to 30cps, 0.04 to 70cps, 0.5 to 130cps, 0.5 to 13cps, 0.5 to 30cps, 0.5 to 70cps, 1 to 130cps, 1 to 20cps, 1 to 50cps, 5 to 25cps or 5 to 75cps) viscosity.
In aspect above-mentioned each, this self-assembled coating can have from the Surface Contact angular lag of 20-120 ° (for example, from 20-60 °, 30-70 °, 40-80 °, 60-90 °, 70-100 °, 80-110 °, 90-120 °, 60-120 ° or 35-90 °).
In aspect above-mentioned each, biologically active agent in this coating can have from 1% to 99%(for example, from 1% to 85%, 5% to 99%, 5% to 85%, 10% to 99%, 10% to 85%, 20% to 99%, 20% to 85%, 30% to 99%, 30% to 85%, 40% to 99% or 50% to 99%) the dissociation constant phosphate buffered saline (PBS).
In aspect above-mentioned each, this biologically active agent can be selected from protein, peptide class, carbohydrate, antibiotics, antiproliferative class, rapamycin Macrolide, anodyne class, narcotic class, anti-angiogenic agent class, antithrombotic agent class, vasoactive agent class, antithrombotics class, immunomodulator class, cytotoxic agent class, antiviral agent class, antibody class, neurotransmitter, psychoactive drug class, oligonucleotide class, vitamins, lipid and their prodrug.In specific embodiments, this biologically active agent (for example is selected from the antiproliferative class, methotrexate, trimetrexate, gemcitabine, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol (taxol), Docetaxel (docetaxel), daunorubicin, Dx, gengshengmeisu, idarubicin, bleomycin and tamoxifen) and rapamycin Macrolide (for example, rapamycin, CCI-779, everolimus and ABT-578).For example, when tissue surface is that vessel wall and this treatment are sent when suppressing vascular restenosis, these reagent may be useful.
In aspect above-mentioned each, this self-assembled coating can be drained.
In aspect above-mentioned each, this mammalian tissues can be in subject.
In a related aspect, feature of the present invention is the temporary medical supply with self-assembled coating surface deposited thereon, this self-assembled coating (for example comprises (i) oligomeric oligopolymer of fluoridizing, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water and (ii) biologically active agent, wherein this temporary medical supply comprises energy generating element, and this energy generating element can be destroyed this self-assembled coating when activating.For example, this energy generating element can produce ultrasonic energy, heat energy, electromagnetic energy or vibrational energy.
In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be any one compound in the formula (I)-(VIII), from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, 4kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 3kDa to 20KDa or from 10kDa to 50KDa) molecular-weight average.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).The graft copolymer that this oligomeric oligopolymer of fluoridizing can be formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be any crosslinked oligomers in the formula (X)-(XIV).In other embodiments, this coating comprises the branch's compound that comprises the insoluble segment of water.This branch's compound can be formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in any compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, 3kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 12kDa to 40KDa or from 15kDa to 50KDa) molecular-weight average.
Further feature of the present invention is the temporary medical supply with surface that self-assembled coating is placed on it, this self-assembled coating (for example comprises (i) oligomeric oligopolymer of fluoridizing, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water and (ii) biologically active agent, wherein this temporary medical supply is deformable temporary medical supply, and this plant machinery ground destroys this self-assembled coating when being launched into deformed configuration.For example, the temporary medical supply of this deformable can be balloon catheter.
In certain embodiments, this coating comprises the oligomeric oligopolymer of fluoridizing.This oligomeric oligopolymer of fluoridizing can be any compound in the formula (I)-(VIII), from 2kDa to 50KDa(for example randomly have, from 2kDa to 5KDa, 4kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 3kDa to 20KDa or from 10kDa to 50KDa) molecular-weight average.In certain embodiments, this oligomeric oligopolymer of fluoridizing is formula (I), (III), (IV), (V) or compound (VI).The graft copolymer that this oligomeric oligopolymer of fluoridizing can be formula (IX).Alternately, this oligomeric oligopolymer of fluoridizing can be any cross-linked polymer in the formula (X)-(XIV).In other embodiments, this coating comprises the branch's compound that comprises the insoluble segment of water.This branch's compound can be formula (XV), (XV-A), (XV-B), (XV-C) or (XVII) in any compound, from 1kDa to 50KDa(for example randomly have, from 1kDa to 5KDa, 3kDa to 12KDa, 6kDa to 15KDa, 5kDa to 25KDa, 12kDa to 40KDa or from 15kDa to 50KDa) molecular-weight average.
In any of above-mentioned temporary medical supply, this coating can have from 0.01 micron to 250 microns the thickness of (for example, from 0.01 micron to 5 microns, 0.1 micron to 5 microns, 1 micron to 5 microns, 1 micron to 25 microns, 2 microns to 25 microns, 5 microns to 50 microns, 5 microns to 100 microns, 10 microns to 250 microns, 15 microns to 50 microns or 20 microns to 125 microns).
In some embodiment of above-mentioned temporary medical supply, this self-assembled coating is by from 1kDa to 60kDa(for example having, from 1kDa to 40kDa, 2kDa to 60kDa, 2kDa to 40kDa, 3kDa to 60kDa, 3kDa to 40kDa, 5kDa to 60kDa, 5kDa to 40kDa, 10kDa to 60kDa or from 15kDa to 60kDa) component of molecular weight forms.
In another other embodiments of above-mentioned temporary medical supply, this oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's compound of the insoluble segment of water from 1kDa to 30kDa(for example has, from 1kDa to 60kDa, 2kDa to 60kDa, 2kDa to 30kDa, 3kDa to 60kDa, 3kDa to 30kDa, 5kDa to 60kDa, 5kDa to 30kDa, 10kDa to 60kDa or from 10kDa to 30kDa) theoretical molecular.
In the specific embodiments of above-mentioned temporary medical supply, this oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's compound of the insoluble segment of water comprises a hard segment, a soft chain segment and poly-fluorine organic group, wherein this oligomeric oligopolymer of fluoridizing comprises from 5% to 80%(w/w) hard segment, from 10% to 90%(w/w) soft chain segment, and from 5% to 80%(w/w) poly-fluorine organic group.
In any of above-mentioned temporary medical supply, this biologically active agent can distribute equably and spread all over this self-assembled coating.
In any of above-mentioned temporary medical supply, this biologically active agent can be attached in this self-assembled coating by the deposition of solids method.
In any of above-mentioned temporary medical supply, this self-assembled coating can comprise from 1% to 30%(w/w) the fluorine atom of fluorine atom (for example, from 2% to 30%, 3% to 30%, 4% to 30%, 5% to 30%, 2% to 10%, 3% to 15% or 4% to 20%(w/w)).
In any of above-mentioned temporary medical supply, this self-assembled coating comprises from 0.1% to 50%(w/w) the biologically active agent of biologically active agent (for example, from 0.1% to 10%, 0.5% to 30%, 1% to 50%, 2% to 50%, 2% to 30%, 3% to 50%, 0.5% to 5%, 0.5% to 10%, 1% to 10%, 2% to 15%, 2% to 25%, 3% to 15% or 3% to 25%(w/w)).
In any of above-mentioned temporary medical supply, this self-assembled coating from 20:1 to 1:20(for example can comprise, from 1:1 to 1:20,20:1 to 1:1,10:1 to 1:10,1:1 to 1:10,10:1 to 1:1,5:1 to 1:5,1:1 to 1:5 or 5:1 to 1:1) oligomeric fluorinated oligomeric thing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's Compound Phase of the insoluble segment of water is for the molar ratio of biologically active agent.
In any of above-mentioned temporary medical supply, this self-assembled coating from-80 ° of C to 40 ° of C(for example can have, from-80 ° of C to 5 ° of C ,-60 ° of C to 5 ° of C ,-50 ° of C to 20 ° of C, 40 ° of C to 30 ° of C ,-30 ° of C to 40 ° of C, 20 ° of C to 40 ° of C or-15 ° of C to 25 ° of C) glass transition temp.
In any of above-mentioned temporary medical supply, this self-assembled coating can have from 1.0 to 200g(for example, from 1.0 to 100g, 1.0 to 50g, 2.0 to 200g, 2.0 to 100g, 2.0 to 50g, 1.0 to 25g, 2.0 to 25g, 3.0 to 75g, 3.0 to 50g, 3.0 to 25g or 1.0 to 20g) sorptive force.
In any of above-mentioned temporary medical supply, this self-assembled coating can have from 0.04 to 130cps(for example, from 20 to 130cps, 50 to 130cps, 75 to 130cps, 0.04 to 30cps, 0.04 to 70cps, 0.5 to 130cps, 0.5 to 13cps, 0.5 to 30cps, 0.5 to 70cps, 1 to 130cps, 1 to 20cps, 1 to 50cps, 5 to 25cps or 5 to 75cps) viscosity.
In any of above-mentioned temporary medical supply, this self-assembled coating can have from the Surface Contact angular lag of 20 °-120 ° (for example, from 20 °-60 °, 30 °-70 °, 40 °-80 °, 60 °-90 °, 70 °-100 °, 80 °-110 °, 90 °-120 °, 60 °-120 ° or 35 °-90 °).
In any of above-mentioned temporary medical supply, this biologically active agent can be selected from protein, peptide class, carbohydrate, antibiotics, antiproliferative class, rapamycin Macrolide, anodyne class, narcotic class, anti-angiogenic agent class, antithrombotic agent class, vasoactive agent class, antithrombotics class, immunomodulator class, cytotoxic agent class, antiviral agent class, antibody class, neurotransmitter, psychoactive drug class, oligonucleotide class, vitamins, lipid and their prodrug.In specific embodiments, this biologically active agent (for example is selected from the antiproliferative class, methotrexate, trimetrexate, gemcitabine, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol (taxol), Docetaxel (docetaxel), daunorubicin, Dx, gengshengmeisu, idarubicin, bleomycin and tamoxifen) and rapamycin Macrolide (for example, rapamycin, CCI-779, everolimus and ABT-578).
In any of above-mentioned temporary medical supply, this self-assembled coating can be drained.
The further feature of the present invention is by following method for biologically active agent being delivered to the internal blood vessel position, comprise temporary medical supply of the present invention is inserted in the blood vessel (vascular), should be positioned near this position by temporary medical supply, and the coating of destroying on this temporary medical supply is delivered to this position with this biologically active agent.
Feature of the present invention is to be inserted in the blood vessel (vascular) and to activate the method that this energy generating element be used for to suppress a position restenosis of blood vessel (vascular) by the temporary medical supply that will comprise energy generating element, and wherein this biologically active agent is selected from antiproliferative class and rapamycin Macrolide.
Feature of the present invention still is launched into the method that deformed configuration is used for suppressing a position restenosis in the blood vessel (vascular) by the temporary medical supply of deformable of the present invention being inserted in the blood vessel (vascular) and with the temporary medical supply of this deformable, and wherein this biologically active agent is selected from antiproliferative class and rapamycin Macrolide.In certain embodiments, the temporary medical supply of this deformable is catheter air bag.The method may further include disease location place stent (for example, can or launch afterwards stent of catheter air bag before launching catheter air bag).Can launch catheter air bag and be used for the treatment of in-stent restenosis.
In aspect being used for the treatment of blood vessel (vascular) above-mentioned each, this blood vessel (vascular) can be bifurcated vessels (vascular).
For example can use TA.XTPlus texture analysis instrument (Stable Micro Systems; Distributed by Texture Technologies Corp; Scarsdale, N.Y.) measure the sorptive force (viscosity) of coating of the present invention, this analyser is measured sorptive force (viscosity) with the form of " gram force ".
" C 1-10Alkyl " word refers to have the branch of 1 to 10 carbon atom (comprising end value) or the stable hydrocarbon group of branch not.Alkyl can comprise monocycle, two ring or three rings alternatively, and wherein each ring has 3 to 6 members ideally.This alkyl group can be that replace or unsubstituted.Exemplary substituting group comprises alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, dibasic amino, season amino, hydroxyalkyl, carboxyalkyl and carboxylic group.
" C 2-10Alkene " word refers to comprise the branch of one or more pairs of keys or the hydrocarbyl group of branch not, has ideally 2 to 10 carbon atoms.C 2-10Alkene can comprise monocycle, two ring or three rings alternatively, and wherein each ring has five or six members ideally.This C 2-10Olefin group can be replacement or unsubstituted.Exemplary substituting group comprises alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, disubstituted amido, season amino, hydroxyalkyl, carboxyalkyl and carboxylic group.
" C 2-10Alkynes " word refers to comprise the branch of one or more triple bonds or the hydrocarbyl group of branch not, has ideally 2 to 10 carbon atoms.C 2-10Alkynes can comprise monocycle, two ring or three rings alternatively, and wherein each ring has five or six members ideally.This C 2-10The alkynes group can be replacement or unsubstituted.Exemplary substituting group comprises alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, dibasic amino, season amino, hydroxyalkyl, carboxyalkyl and carboxylic group.
" C 5-10Aryl " or " aryl " word refer to have aromatic group (for example, phenyl or imidazoles) with the loop systems of conjugated pi electron.The ring of this aromatic yl group is 5 to 10 atoms preferably.This aromatic ring can comprise uniquely that carbon atom maybe can comprise carbon atom and heteroatomic mixing.Preferred heteroatoms comprises nitrogen, oxygen, sulphur and phosphorus.Aromatic yl group can comprise monocyclic, bicyclic or tricyclic alternatively, and wherein each ring preferably has five or six members.This aromatic yl group can be replacement or unsubstituted.Exemplary substituting group comprise alkyl, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, single substituted-amino, disubstituted amido and season amino group.
As used herein, " C " refers to a chain end group.Exemplary chain end group comprises the simple function group that comprises amine, alcohol or carboxylic functionality.
As used herein, " complexing " or " complexing action " refers to non-covalent also or by being coordinated to the interaction on the metal center between the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) that comprises or the complexing in the branch's compound that comprises the insoluble segment of water part and the biologically active agent in self-assembled coating of the present invention.The example of non-covalent binding interactions that can be used according to the invention (for example includes but not limited to hydrogen bond, ionic interaction, dipole-dipole interaction, ion pair and salt formation), clathrate complex, clathration (clathration), Van der Waals interact (for example, π-π stacking (pi-pi stacking)) and their combination.This interaction can also be via being coordinated to metal center by complexing part and biologically active agent.In some instances, this biologically active agent comprises the metal center that is coordinated on this complexing part.
As used herein, " complexing part " refers to certain embodiments of the present invention, be included in the oligomeric fluorinated oligomeric thing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) that comprises in the self-assembly systems of the present invention or a part that comprises branch's compound of the insoluble segment of water, this part by noncovalent interaction also or be coordinated to complexing biologically active agent on the metal center forms a kind of polymer complexes.This complexing part can be electrically charged part, for example loses the part of proton under physiological pH, becomes thus electronegative (for example, carboxylicesters or phosphodiester); Under physiological pH, obtain the part of proton, become thus positively charged (for example, ammonium, guanidine (guanidinium), amidine (amidinium)); Comprise without the part (for example, quaternary ammonium) of the clean form positive charge of protonation or comprise part (for example, borate, the BR of the clean form negative charge that does not lose proton 4 -).Exemplary charged complexing partly includes but not limited to carboxylate salt, phosphodiester, phosphoramidate, borate, phosphoric acid salt, phosphonate, phosphoric acid ester, sulfonate, vitriol, thiolate, phenates, ammonium, amidine, guanidine, quaternary ammonium and imidazoles functional group.This complexing part can be designed in whole or in part this biologically active agent of physical package, for example cyclodextrin.This complexing part can be designed to be connected to complementary oligonucleotide and/or the peptide sequence that exists in the biologically active agent.This complexing part can be designed to metal center of coordination, comprises that this biologically active agent as independent part also or comprise this metal center.In U.S. Patent Publication No. 20070037891, illustrated how to make complexing part and with the explanation of biologically active agent complexing, be combined in by reference this.
As used herein, " covalently be connect (covalency tethers, covalently tethered) " refers to the part of separating by one or more covalent linkage.For example, when thereby oligomeric fluorinated groups covalently is to link when forming the oligomeric oligopolymer of fluoridizing on the oligopolymer, system connects that (tethers tethered) comprises two parts that the part of separating by a singly-bound and the LinkB segment that all covalently is attached to it by for example two parts separate.
Term " loop systems " refers to comprise the compound of one or more covalently closed circle structures, and the atom that wherein forms this ring main chain is by following any constituting: carbon, oxygen, nitrogen, sulphur and phosphorus.This loop systems can be replacement or unsubstituted.Exemplary substituting group include but not limited to alkyl, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, halogen, fluoroalkyl, carboxyl, carboxyalkyl, amino, aminoalkyl, mono-substituted amino, dibasic amino and season amino group.
As used herein, " dissociation constant in the phosphate buffered saline (PBS) " refers in the equilibrium distribution of biologically active agent under 25 ° of C between coating of the present invention and phosphate-buffered saline (137mM NaCl, 2.7mM KCl, 10mM Sodium phosphate dibasic, 2mM potassium primary phosphate and pH 7.4).Dissociation constant in the phosphate buffered saline (PBS) is expressed as the per-cent of the biologically active agent that exists in this phosphate buffered salt solution under equilibrium state, and measures by the equal amount of the biologically active agent that is placed on coating of the present invention in the phosphate buffered saline (PBS) and determines to exist in this aqueous solution.
As used herein, " can drain " branch's compound of referring to the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprising the insoluble segment of water from the surface of temporary medical supply or be coated with the diffusion of the tissue surface of self-assembled coating of the present invention.Can drain coating and be and wherein when being dissociated by self-assembled coating of the present invention, only produce and to drain and need not the oligomeric oligopolymer of fluoridizing of hydrolytic deterioration (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise those coatings than minor comonomer of branch's compound of the insoluble segment of water by kidney or liver and gall.
" assorted alkyl " word refers to wherein one or more methylene radical (CH 2-) branch that partly replaced by nitrogen, oxygen, sulphur, carbonyl, thiocarbonyl (thiocarbonyl), phosphoryl or alkylsulfonyl or the alkyl group of branch not.Some examples comprise tertiary amines, ethers, thioether class, amides, thioamide analog (thioamides), amino formate (carbamates), thiocarbamates, phosphoramidate class, sulfamido and disulfides.Assorted alkyl can comprise monocycle, two ring or three rings alternatively, and wherein each ring has three to six members ideally.Should assorted alkyl group can be that replace or unsubstituted.Exemplary substituting group comprises alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, halogen, hydroxyl, fluoroalkyl, perfluoroalkyl, amino, aminoalkyl, dibasic amino, season amino, hydroxyalkyl, carboxyalkyl and carboxylic group.
As used herein, " LinkB " refer to can be covalently bound or the coupling segment of oligopolymer, biologically active agent and/or the oligomeric fluorin radical of complexing.Typically, the LinkB molecule has the molecular weight of scope from 40 to 700.Preferably, these LinkB molecules are selected from the group that is comprised of the Diamines of functionalization, diisocyanates, disulfonic acid class, omega-dicarboxylic acids, diacid chloride class and twain-aldehyde compound, and wherein the component of this functionalization has the second chemically attached functionalized chemical part for assessment of oligomeric fluorin radical.This class second group comprises for example lipid, metal carboxylate, Sulfonates, phosphonates, thio-alcohol, vinyl-based (vinyls) and secondary amine class.Thereby terminal hydroxyl class, amine or carboxylic-acid on oligomeric intermediates can form the oligoamide class with the Diamines reaction; Thereby form low polyurethanes, low polyureas, oligoamide class with di-isocyanate reaction; Thereby form oligomeric Sulfonates, oligomeric sulfamido with the reaction of disulfonic acid class; Thereby form oligomer ester class, oligoamide class with the dicarboxylic acid reaction; Thereby form oligomer ester class, oligoamide class with the diacid chloride reaction; Thereby and react formation with twain-aldehyde compound and hang down polyacetal, oligomeric imines class.
As used herein, " inhibition restenosis " refers to and not existing any further treatment to treat under the restenosis risk so that contingent again narrowing down compared after removing obstruction to solve, uses methods for the treatment of of the present invention to reduce afterwards artery in treatment with removing obstruction (for example angioplasty) and again narrow down.
As used herein, term " not organic segment of halogenation " refers to not comprise the organic oligomer (for example, having 100-3, the molecular weight between the 500Da) of any halogen group (that is, F, Cl, Br or I).This is organic segment preferably water-soluble (for example, polyoxyethylene glycol) of halogenation not.
As used herein, term " the oligomeric oligopolymer of fluoridizing (oligomer that oligomerization is fluoridized, oligofluorinated oligomer) " refers to covalently be connected to the oligopolymer on the oligomeric fluorin radical.The oligomeric oligopolymer of fluoridizing for example comprises among this described formula I-XIV any those again.
" oligomeric (oligomerization; oligo) " or " oligopolymer (oligomer, oligomer) " word refers to one or more repeating units of shorter length, normally less than approximately 500 monomeric units and molecular weight less than 10,000 still preferably＜5,000Dalton.Preferably, oligopolymer is selected from by in the following group that forms: polyurethane(s), polyureas, polyamide-based, polyoxyalkylene (polyalkylene oxide base), polycarbonate, polyester, polylactone, silicone, polyethersulfone, polyolefine, polyethylene, polypeptide, polysaccharide; And ether connects segment with the amine of being connected.
" can absorb again " when a part that a word refers to the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water is designed in being incorporated into mammalian tissues and be absorbed again.For example, oligomeric fluorinated oligomeric thing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) or the oligopolymer part that comprises branch's compound of the insoluble segment of water can be selected from can resorbent polymer class, for example polyester (for example, poly(lactic acid), polyglycolic acid and their mixture), they can be decomposed and assimilate in mammalian tissues.
As used herein, term " trifunctional monomer " refers to comprise the small molecules (for example, have between the 50-3500Da molecular weight) that can form with another compound (for example, any of joint described herein) three functional groups of covalent linkage.Exemplary trifunctional monomer comprises three alcohols, tricarboxylic acids and acid derivative class and triisocyanate class.The trifunctional monomer that can be used for composition described herein, method and temporary medical supply comprises glycerine, TriMethylolPropane(TMP) (TMP), trimethylolethane (TME), trimesic acid (TMA), three (hydroxyethyl) chlorinated isocyanurates (THEIC), tetramethylolmethane, pyromellitic acid, 1,3,5-trihydroxybenzene, Triaminopyrimidine or melamine.
As used herein, term " temporary medical supply " refers to be designed to only temporarily rest on equipment in health or the mammalian tissues (for example, only carrying out medical procedures and/or biologically active agent is delivered in the process of target tissue).After being delivered to the tissue for the treatment of, biologically active agent in 30 minutes, should remove by temporary medical supply.
As used herein, term " the insoluble segment of water (water-insoluble segment, water-fast segment; water insoluble segment) " refer to can not with the miscible organic oligomeric segment of water (for example, has 200-3,500Da or 100-1, the molecular weight between the 500Da).The insoluble segment of exemplary water comprises the organic segment of poly-fluorine described herein and polysiloxane or polyolefins and other oligopolymer classes described herein.
From following detailed description, accompanying drawing and claims, other features of the present invention and advantage will become clear.
Description of drawings
Fig. 1 is a graphic extension, and it has been described and has fluoridized drug delivery composition and angiopoiesis airbag coatings.This fluorine containing regions (fluoro-domain) provides the shield (shielding) (because its intrinsic water exhaust characteristic) of restriction solubleness during medicinal composition (covalency and non-covalent) is delivered to illing tissue.Can select by this way these chemical actions of not fluoridizing segment to be used in transferring to the process of illing tissue producing good combination with balloon surface.
Fig. 2 is a graphic extension, and it has described the expansion that applies air bag in the blood vessel (vascular) that blocks (obturation).In the second picture frame, because air bag launches at the illing tissue position, this is sent molecule and has lost the ability that they form continuous film, causes thus the oligomeric molecule of fluoridizing of medicine and this to separate, and these molecules begin in the hydration of medicine combining site now.In the 3rd picture box, no longer observe this and send molecule, because it has been dissolved in the blood flow, it can be eliminated by the kidney system there.
Fig. 3 is the photo of the nylon membrane that is coated with compound 1 of expression BSA incubation, and only compares with the nylon membrane of BSA incubation, and it has shown albumen absorption (mazarine deposition) still less.BSA dyes with Xylene Brilliant Cyanine G R dyestuff.
Embodiment
Method and composition feature of the present invention is a kind of self-assembled coating or preparation, comprise oligomer compound (the oligomeric oligopolymer of fluoridizing for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain for example, or comprise branch's compound of the insoluble segment of water), preferred branch compound, and biologically active agent.This biologically active agent can be attached in this coating or the preparation in many ways, comprise by with the non-covalent complexing of the oligomeric oligopolymer of fluoridizing of carrying complexing part (for example, be attached among LINKB, oligopolymer or the FT), by covalently bound to the oligomeric oligopolymer of fluoridizing, as the physics inclusion.
By self-assembly oligomer compound (for example, the oligomeric oligopolymer of fluoridizing, the oligomeric oligopolymer of fluoridizing of side chain or straight chain for example, or comprise branch's compound of the insoluble segment of water), preferably (this branch's compound (for example comprises a kind of core oligopolymer, the insoluble segment of water to branch's compound, the segment of fluoridizing), the site, a common location that and alternatively is used for biologically active agent) form easily coating of the present invention and preparation.These coatings and preparation can have good blood compatibility (low blood activity), and can be (are easy to eliminate in body and need not the location, this can cause the reduction of chronic local inflammation) that can drain.This centronucleus effect allows delivery platform to be attached on polymkeric substance or the metal intervening equipment.The insoluble segment of this water (for example, the segment of fluoridizing) it is critical being down to minimum for blood activation in the blood environment that will flow, be used for shielding this biologically active agent and (for example avoid environmental attack, because the solvency action before arriving therapentic part is also or because folding in delivery process, the degraded of the reagent that sorptive force (viscosity) loss causes in the equipment of unfolding or change shape and too early release) until be delivered to the illing tissue position, and with this oligomer compound (for example be used for, the oligomeric oligopolymer of fluoridizing), preferably branch's compound is self-assembled into be used to the self-assembled coating that comprises biologically active agent.This optional biologically active agent binding site allows this delivery system compatible from extensively various different therapeutical agents.But the draining features of this self-assembled coating and preparation is the part of a strategy, be used for allowing dissolving simply and eliminating carrier molecule, rather than keep or release original position degraded product, these degraded products cause some drugs FirebirdTM feature the proinflammatory event (referring to Virmani R, Semin Interv Cardiol 3 (3-4): 163 (1998); Ross et al., Adv Exp Med Biol 102:135 (1978); And Barker SG, Atherosclerosis105 (2): 131 (1994)).
The oligomeric oligopolymer of fluoridizing and the branch's compound that comprises the insoluble segment of water
The oligomeric oligopolymer of fluoridizing and poly-fluorine organic group
The oligomeric oligopolymer of fluoridizing comprise covalently bound to oligomeric fluorin radical oligopolymer and can by but be not limited to that any describes among the formula I-XIV.
This oligomeric oligopolymer of fluoridizing can be the polymkeric substance that through type (I) illustrates:
F T–(oligo)–F T （I），
F wherein TBe poly-fluorine organic group, and oligo is oligomeric segment.
This oligomeric oligopolymer of fluoridizing can be the polymkeric substance that through type (II) illustrates:
Figure BDA00002022515600221
(i) F wherein TBe covalently bound poly-fluorine organic group to LinkB, (ii) C is the chain termination group, and (iii) Oligo is oligomeric segment, (iv) LinkB is the coupling segment, and (v) is the integer (for example, from 1 to 50 greater than 0,1 to 20, or 1 to 10 integer).
This oligomeric oligopolymer of fluoridizing can be the polymkeric substance that through type (III) illustrates:
F T–[B–(oligo)] n-B–F T（III），
Wherein B comprise carbamate (urethane, urethane); Oligo is oligomeric segment; F TIt is poly-fluorine organic group; And n is from 1 to 10 integer.
At formula (I), (II), and (III), oligo can be the branch of 1 to 20 repeat unit or the oligomeric segment of branch not, for example comprise following oligomeric segment: polyurethane(s), polyureas, polyamide-based, (comprising the polypeptide class), polyoxyalkylene (polyalkylene oxide), polycarbonate, polyester, polylactone, silicone, polyethersulfone, polyolefine, polythene derivative, polypeptide, polysaccharide, polysiloxane, polydimethylsiloxane, polyethylene-butylene, polyisobutene, polyhutadiene, poly(propylene oxide) (comprises neopentyl glycol, and poly propylene oxide derivative class), oxyethane, the polytetramethylene oxide compound (polybutylene oxide, polytetramethyleneoxide), or polyvinylidene segment.In specific embodiments, oligo comprises poly(propylene oxide), polyethylene oxide or polytetramethylene oxide compound (polytetramethyleneoxide).
This oligomeric oligopolymer of fluoridizing can be the polymkeric substance that through type (IV) illustrates:
F T–[B–A] n–B–F T （IV），
Wherein (i) A is a soft chain segment, the polyhutadiene, poly-(2 that comprises hydrogenation, 2-dimethyl-1-3-propyl carbonate), polyhutadiene, poly-(Diethylene Glycol) adipic acid ester, poly-(cyclohexyl carbonic ether) (poly (hexamethylene carbonate)), poly-(ethene-altogether-butylene), neopentyl glycol-Tetra hydro Phthalic anhydride polyester, Diethylene Glycol-Tetra hydro Phthalic anhydride polyester, 1,6-hexylene glycol-Tetra hydro Phthalic anhydride polyester or bisphenol A ethoxy thing; (ii) B is a hard segment, comprises carbamate (urethane); (iii) F TIt is a poly-fluorine organic group; And (iv) n is from 1 to 10 integer.For example, this hard segment can form by being selected from following vulcabond: 3-isocyanato methyl, 3,5,5-3-methyl cyclohexanol based isocyanate, 4,4 '-methylene radical two (cyclohexyl isocyanate), 4,4 '-methylene radical two (phenyl) isocyanic ester, Toluene-2,4-diisocyanate, 4 vulcabond, a tetramethylxylene diisocyanate and hexamethylene diisocyanate; And n can be 1 or 2.
This oligomeric oligopolymer of fluoridizing can be by formula V or (VI) explanation polymkeric substance:
Figure BDA00002022515600231
Or
Figure BDA00002022515600232
Wherein (i) A is a soft chain segment; (ii) B is a hard segment, comprises chlorinated isocyanurates tripolymer or biuret tripolymer; (iii) B ' is a hard segment, comprises carbamate (urethane); (iv) each FT is poly-fluorine organic group; And (v) n is the integer between 0 to 10.Soft chain segment can have 500 to 3, the number-average molecular weight of 500Dalton (Mn), and the polyhutadiene (HLBH), poly-(2 that comprises hydrogenation, 2-dimethyl-1-3-propyl carbonate) (PCN), the polyisoprene (HHTPI) of polyhutadiene (LBHP), polytetramethylene oxide compound (PTMO), Diethylene Glycol-Tetra hydro Phthalic anhydride polyester (PDP), hydrogenation, poly-(hexa-methylene carbonic ether), poly-(2-butyl-2-ethyl-1,3-propyl carbonate) or hydroxy-end capped polydimethylsiloxaneblock block copolymers (C22).Can be by making triisocyanate and comprising that the glycol of soft chain segment reacts to form this hard segment, wherein this triisocyanate is selected from hexamethylene diisocyanate (HDI) biuret tripolymer, isophorone diisocyanate (IPDI) tripolymer or hexamethylene diisocyanate (HDI) tripolymer.
Alternately, coating of the present invention comprises that covalency system connects or is complexed to biologically active agent on the oligomeric oligopolymer of fluoridizing.The oligomeric oligopolymer of fluoridizing like this can illustrate by through type (VII):
Figure BDA00002022515600241
Wherein oligo is oligomeric segment; Bio is biologically active agent; F TIt is oligomeric fluorin radical; Each LinkB is covalently bound to oligo, F T, or Bio on organic moiety, a is the integer (for example, 1-50,1-20,1-10 or 1-5) greater than 0; B and c are the integer (for example, 1-20,1-10,1-5,2-20,2-10 or 2-5) more than or equal to 0 independently of one another; And d is 0 or 1.This oligopolymer can comprise polyurethane(s), polyureas, polyamide-based, polyalkylene oxides (polyalkylene oxide), polycarbonate, polyester, polylactone, silicone, polyethersulfone, polyolefine, polyethylene, polypeptide, polysaccharide or their combination.
In some coating, this self-assembled coating is to be formed by the oligomeric oligopolymer of fluoridizing that comprises the poly-fluorine organic group of non-end, for example those of formula (VIII):
C–(LinkB)–[F T–(LinkB)] a–C （VIII），
(i) F wherein TWith the poly-fluorine organic group of the covalently bound difunctionality to LinkB in two ends; (ii) C is a chain capping group; (iii) LinkB is a coupling segment; And (iv) a is the integer (for example, 1-50,1-20,1-20,1-5,2-20,2-10 or 3-20) greater than 0.
This self-assembled coating can form from the graft copolymer that illustrates by (IX):
Figure BDA00002022515600242
Wherein [OLIGO] is the oligopolymer polymer segment; [LINKA] is the first coupling segment, and it connects at least two [OLIGO] thereby group forms (([OLIGO]-[LINKA]) that has less than 15,000Da theoretical molecular a)-[OLIGO])); T is a capping group; F TIt is poly-fluorine organic group; [MRF] is a kind of polyolefine; [INI] has the functional group of causing ATRP, atom transferred free radical addition reaction (ATRA) or atom transfer group cyclization (ATRC) ability; [LINKB] is the second coupling segment, and it is with (([OLIGO]-[LINKA]) a)-[OLIGO])) be connected to F TOn, be connected on the T, and/or be connected on [LINKC]; [LINKC] is the 3rd coupling segment, and it is connected to [LINKB] on [INI], perhaps, do not exist in [INI] situation, [LINKC] be the n dendroid in generation (group) (dendron); [promoting agent] is that complexing or covalency system connect one or more biologically active agents on (tether) to [LINKC] or [MRF]; Each a and d are the integer (for example, 1-20,1-10 or 1-5) greater than 0 independently, and n is from 1 to 150 integer (for example, 1-50,1-20,1-10 or 1-5); P is from 1 to 20 integer (for example, 1-10,1-5 or 2-10); And each m, p, y and w are 0 or from 1 to 20 integer (for example, 1-10,1-5 or 2-10) independently; Condition is m≤n, w≤y, and when m, p, y and w were 0, then n was from 2 to 150 integer, when z 〉=1, m=0 then, and when m 〉=1, then z=0.Be somebody's turn to do (([OLIGO]-[LINKA]) a)-[OLIGO])) part can comprise and be selected from following polycondensate: polyurethane(s), polyureas, polyamide-based, polyalkylene oxide, polycarbonate, polyester, polylactone, silicone, polyethersulfone, polypeptide, polysaccharide, polysiloxane, polydimethylsiloxane, poly(propylene oxide), polyethylene oxide, polytetramethylene oxide compound and their combination.Should [MRF] part can be selected from polyacrylic acid, polymethyl acrylic acid, poly-(hydroxyethyl methylacrylate), poly-(Hydroxyethyl acrylate), poly-(methyl alkyl sulfoxide methacrylic ester) (poly (methylalkylsulfoxide methacrylate)), poly-(methyl alkyl sulfoxide acrylate) (poly (methylalkylsulfoxide acrylate)), polyacrylamide, poly-(Methacrylamide), poly-(DMAA), poly-(N-sec.-propyl-acrylamide), poly-(vinyl alcohol), PVP, poly-(N-caprolactam), and their multipolymer.This oligomerization or oligopolymer part can include but not limited to polyurethanes, polyureas, polyamide-based, the polyalkylene oxide class, polycarbonate-based, polyester, the polylactone class, silicone, polyether sulfone, polyolefins, the polythene derivative class, the polypeptide class, polyose, polysiloxane-based, the polydimethylsiloxane class, polyethylene-butylene, the polyisobutene class, polybutadiene, polyoxypropylene series, the polyethylene oxide class, polytetramethylene is oxide-based, the polyvinylidene class, polycaprolactone, poly(lactic acid), polyoxyethylene glycol, polypropylene glycol, poly-Diethylene Glycol phthalic ester, poly-Diethylene Glycol adipic acid ester, poly butyric ester (polyhydroxybutyrate), poly-Hydroxyoctanoic acid ester (polyhydroxyoctanoate), poly-hydroxyl valerate (polyhydroxyvalerate), biOH TMSoybean oil derivative (Cargill) and their combination and mixture.
This self-assembled coating can be from monomer form polymer coated, this monomer comprises (i) two or more crosslinking structure territories, and (ii) oligomeric segment, having covalency is the first end of linking on the first crosslinking structure territory, and covalency system links the second end on the second crosslinking structure territory, and wherein at least one is a kind of oligomeric crosslinking structure territory of fluoridizing in this crosslinking structure territory.This monomer further through type (I) illustrates:
(D)–[(oligo)–(D)] n （X），
Wherein oligo is oligomeric segment; Each D is the crosslinking structure territory; And n is from 1 to 20,1 to 15,1 to 10,1 to 8 or 1 to 5 integer, and wherein at least one D is oligomeric crosslinking structure territory of fluoridizing.Alternately, this monomer can further specify by through type (XI):
(D)–[(oligo)–(LinkA-F T)] m–[(oligo)–(D)] n （XI）,
Wherein oligo is oligomeric segment; Each D is the crosslinking structure territory; F TIt is oligomeric fluorin radical; Each LinkA-F TTo be covalently bound to an oligo(oligopolymer), the 2nd oligo(oligopolymer) and F TOn organic moiety; N is from 1 to 20 integer (for example, 1-10,1-5 or 2-10); And m is from 1 to 20 integer (for example, 1-10,1-5 or 2-10), and wherein at least one D is oligomeric crosslinking structure territory of fluoridizing.Can comprise for the preparation of the crosslinking structure territory of coating of the present invention the reactive moieties that can carry out chain growth polymerization reaction, such as, but not limited to vinyl-based, epoxides, aziridines, Yi Ji the oxazoline class.For example, this crosslinking structure territory is selected from:
Figure BDA00002022515600261
And
Figure BDA00002022515600262
This monomer can further specify by through type (XII):
(oligo) n(vinyl) m(F T) o(XII),
Wherein oligo is oligomeric segment; Vinyl (vinyl) is the crosslinking structure territory, comprises the unsaturated part of the polyreaction that can stand the free radical initiation; F TThat covalency system links this vinyl and/or oligo(oligopolymer) on oligomeric fluorin radical; And each n, m and o are from 1 to 5 integer independently, and wherein this monomer comprises at least one oligomeric crosslinking structure territory of fluoridizing.This monomer further through type (XIII) illustrates:
F T-LinkA-[-(oligo) a-(LinkA) b] c-F T (XIII)
| |
The ethylene vinyl base
Wherein oligo is oligomeric segment; Vinyl is the crosslinking structure territory, comprises the unsaturated part of the polyreaction that can stand the free radical initiation; F TIt is oligomeric fluorin radical; Each LinkA is covalently bound to oligo, F T, and vinyl on organic moiety; And each a, b and c are the integer (for example, 1-20,1-10,1-5,2-10 or 2-5) greater than 0 independently.Can be by making for example vinylformic acid of the monomer that carries the crosslinking structure territory and the vinyl compound of not fluoridizing, methyl acrylate, ethyl propenoate, n-butyl acrylate, vinylformic acid 2-hydroxyethyl ester, n-butyl acrylate, glycidyl acrylate, vinyl acrylate, allyl acrylate, vinylformic acid 2-hydroxyethyl ester, methacrylic acid 2-hydroxyethyl ester (HEMA), methacrylic acid 2-amino-ethyl ester, monomethyl vinylformic acid glyceryl ester, acrylamide, Methacrylamide, N-(3-aminopropyl) Methacrylamide, crotonamide, vinyl carbinol, or 1,1,1-trimethyl propane mono allyl ether mixes to prepare that this is polymer coated.
This self-assembled coating can be from monomer form polymer coated, this monomer comprises (i) first component, has by the core of m nucleophilic group replacement, wherein m 〉=2; And second component, have the core that is replaced by n electrophilic group, wherein n 〉=2 and m+n〉4; Wherein said composition comprises at least one oligomeric nucleophilic group of fluoridizing or an oligomeric electrophilic group of fluoridizing, thereby and wherein this first component and second component react and form the oligomeric cross-linked polymer of fluoridizing.This monomer can further specify by through type (XIV):
F T-LinkA-[-(oligo) a-(LinkA) b] c-FT (XIV)，
| |
G G
Wherein oligo is oligomeric segment; G be nucleophilic group also or electrophilic group; F TIt is oligomeric fluorin radical; Each LinkA is covalently bound to oligo, F T, and G on organic moiety; And each a, b and c are the integer (for example, 1-20,1-10,1-5,2-10 or 2-5) greater than 0 independently.Polymer coated in order to form this, these nucleophilic groups and electrophilic group experience nucleophilic substitution reaction, nucleophilic addition or both when mixing.These nucleophilic groups can be selected from but be not limited to: primary amine class, secondary amine class, thio-alcohol, alcohols and phenols.These electrophilic groups can be selected from but be not limited to: oh group, succinimide ester, sulfosuccinimide ester, dimaleoyl imino and the ethene alkylsulfonyl of carboxylic acid esters, chloride of acid group class, anhydrides, isocyanato, isothiocyanic acid base, epoxides, activation.Ideally, the quantity of nucleophilic group is the quantity that is substantially equal to electrophilic group in the mixture (that is, the mole number of nucleophilic group is about 2:1 to 1:2 with respect to the ratio of the mole number of electrophilic group, or even is about 1:1) in the mixture.
In each of following formula, this oligomeric fluorin radical, F T, can be to have 100-1, the poly-fluoroalkyl of molecular weight between the 500Da.For example, F TCan be selected from by general formula CF 3(CF 2) rCH 2CH 2-(wherein r is 2-20) and CF 3(CF 2) s(CH 2CH 2O) χIn the group that the group of (wherein χ is that 1-10 and s are 1-20) forms; Or F TCan be selected from by general formula CH mF (3-m)(CF 2) rCH 2CH 2-and CH mF (3-m)(CF 2) s(CH 2CH 2O) χ-the group that forms of group in, wherein m is 0,1,2 or 3; χ is the integer between 1-10; R is the integer between 2-20; And s is the integer between 1-20.In each of following formula, F TCan be selected from (CF 3) (CF 2) 5CH 2CH 2O-, (CF 3) (CF 2) 7CH 2CH 2O-, (CF 3) (CF 2) 5CH 2CH 2O-, CHF 2(CF 2) 3CH 2O-and (CF 3) (CF 2) 2CH 2O-, 1H, 1H, 2H, 2H-perfluor-1-decanol, 1H, 1H, 2H, 2H-perfluor-1-octanol, 1H, 1H, 5H-perfluor-1-amylalcohol and 1H, 1H, perfluor-n-butyl alcohol and their mixture.
The amount that is loaded into the biologically active agent in this coating will depend on the design of oligopolymer and combine with the releasing curve diagram of hope.This oligopolymer can design and be designed to for the concrete reagent of sending provides concrete application necessary biocompatibility.
Generally, the oligomeric oligopolymer of fluoridizing that in method of the present invention and composition, uses, and those of through type I-XIV explanation can be such as U.S. Patent number 6,127,507 and 6,770,725; PCT publication number WO20007/004067, WO2007/148230, WO2008/076345 and WO2009/043174; And the described preparation of PCT application number PCT/US2009/55418 of submitting on August 28th, 2009, they each is combined in this by reference.
The branch's compound that comprises the insoluble segment of water
The branch's compound that comprises the insoluble segment of water comprise through type (XV), (XV-A), (XV-B), (XV-C) and (XVII) in the compound of each explanation.
This branch's compound can be the compound of formula (XV):
Figure BDA00002022515600281
Wherein m and n both 0, or m and n both 1; Each A and A 2It is the trifunctional monomer with molecular weight between the 50-300Da; Each L and L AJoint independently; Each R X1A, R X1B, R X2A, and R X2BTo have 100-1 independently, the insoluble segment of the water of molecular weight between the 500Da; And R Y1To have 100-1, organic segment of the not halogenation of molecular weight between the 500Da; And as m and n both 1 time, each R Z1And R Z2The insoluble segment of difunctionality water with molecular weight between the 50-800Da independently, perhaps as m and n both 0 time, each R Z1And R Z2To have 100-1 independently, the insoluble segment of the water of molecular weight between the 500Da.
This branch's compound can be the compound of formula (XV-A):
Figure BDA00002022515600291
Wherein A is the trifunctional monomer with molecular weight between the 50-300Da; Each L is joint independently; R Z1And R Z2To have 100-1 independently of one another, the Organohalogen compounds segment of molecular weight between the 500Da; And R Y1To have 100-1, organic segment of the not halogenation of molecular weight between the 500Da.In some embodiments, R Z1And R Z2It is the glycol of fluoridizing.
This branch's compound can be the compound of formula (XV-B):
Figure BDA00002022515600292
Wherein each A, A 2, L, L A, R X1A, R X1B, R X2A, R X2B, R Y1, R Z1, and R Z2As defining described in the formula (XV).
For example, in formula (XV), (XV-A) or (XV-B) each, A can be derivative from trivalent alcohol, or be selected from following trifunctional part: for example, glycerine, TriMethylolPropane(TMP) (TMP), trimethylolethane (TME), trimesic acid (TMA) or three (hydroxyethyl) chlorinated isocyanurates (THEIC).In certain embodiments, R Y1The polyoxyethylene glycol, the zwitter-ion that are straight or branched (comprise the zwitterionics part, for example, the alkyl betaine class, as, alkylamide propyl-betaine, sultaine class and alkylsulphonic acid betaines (alkyl sultaines), alkyl oxide hydroxypropyl sulphonic acid betaine class (alkyl ether hydroxyl propyl sultaines) and alkylamide propyl hydroxyl sulfoacid betaines (alkylamidopropylhydroxy sultaines)) or polyvinylpyrrolidone.In other embodiments, R Z1And R Z2Poly-fluorine organic group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BPoly-fluorine organic group independently.In another other embodiments, R Z1And R Z2The silicone group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BThe silicone group independently of one another.
The branch's compound that comprises the insoluble segment of water can be the compound of formula (XV-C):
Figure BDA00002022515600301
F wherein TIt is poly-fluorine organic group; L is joint; X 1H, CH 3, or CH 2CH 3
X 2H, CH 3, or CH 2CH 3And n is from 5 to 50 integer.
The joint that comprises branch's compound of the insoluble segment of water can illustrate by through type (XVI):
G 1-(Z 1) o-(Y 1) u-(Z 2) s-(R 10)-(Z 3) t-(Y 2) v-(Z 4) p–G 2 （XVI）
G wherein 1It is a key between described poly-fluorine organic group and described joint; G 2It is a key between described joint and Sauerstoffatom; Z 1, Z 2, Z 3, and Z 4Be selected from independently of one another O, S and NR 11R 11Hydrogen or C 1-10Alkyl group; Y 1And Y 2To be selected from independently of one another carbonyl, thiocarbonyl, alkylsulfonyl or phosphoryl; O, p, s, t, u and v are 0 or 1 independently of one another; And R 10To replace or unsubstituted C 1-10Assorted alkyl, the C of alkyl, 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems of aryl, 3 to 10 atoms ,-(CH 2CH 2O) qCH 2CH 2-(wherein q is 1 to 10 integer), or with G 1-(Z 1) o-(Y 1) u-(Z 2) s-be connected to-(Z 3) t-(Y 2) v-(Z 4) p– G 2On chemical bond.In certain embodiments, this joint be covalent linkage or-(C=O)-group.
The branch's compound that comprises the insoluble segment of water can be the compound of formula (XVII):
Figure BDA00002022515600302
F wherein TIt is poly-fluorine organic group; L 2To replace or unsubstituted C 1-10Assorted alkyl, the C of alkyl, 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems of aryl, 3 to 10 atoms ,-(CH 2CH 2O) qCH 2CH 2-(wherein q is 1 to 10 integer); X 1H, CH 3, or CH 2CH 3X 2H, CH 3, or CH 2CH 3And n is from 5 to 50 integer.In certain embodiments, this poly-fluorine organic group is to have 100-1, the poly-fluoroalkyl of molecular weight between the 500Da.In other embodiments, this poly-fluorine organic group is general formula CF 3(CF 2) rCH 2CH 2-or CF 3(CF 2) s(CH 2CH 2O) χ-group, wherein r is the integer from 2-20, χ is the integer from 1-10, and s is the integer from 1-20.In another other embodiments, this poly-fluorine organic group is general formula CH mF (3-m)(CF 2) rCH 2CH 2-or CH mF (3-m)(CF 2) s(CH 2CH 2O) χ-group, wherein m is 0,1,2 or 3; χ is the integer between 1-10; R is the integer between 2-20; And s is the integer between 1-20.In certain embodiments, this poly-fluorine organic group is to be selected from (CF 3) (CF 2) 5CH 2CH 2O-, (CF 3) (CF 2) 7CH 2CH 2O-, (CF 3) (CF 2) 5CH 2CH 2O-, CHF 2(CF 2) 3CH 2O-and (CF 3) (CF 2) 2CH 2O-, 1H, 1H, 2H, 2H-perfluoro-1-decanol, 1H, 1H, 2H, 2H-perfluoro-1-octanol, 1H, 1H, 5H-perfluoro-1-amylalcohol and 1H, 1H, perfluoro-n-butyl alcohol and their mixture.
The insoluble segment of water
Branch described herein compound (for example, formula (XV), (XV-A), (XV-B), (XV-C) and composition (XVII)) comprises the insoluble segment of water.The insoluble segment of exemplary water comprises perfluor organic group class (for example, FT group described herein), polysulfones, aromatic polyimide class and amides.Other comprise polysiloxane-based, polyolefins for example C10, C12 and other saturated or unsaturated hydro carbons.
Joint
The branch's compound (for example, formula (XV), (XV-A), (XV-B), (XV-C) and composition (XVII)) of the insoluble segment of water that comprises described herein comprises joint.The most simply, shank of the present invention is a key between organic segment of trifunctional monomer and Organohalogen compounds segment (for example, poly-fluorine organic group) or not halogenation.This joint can be the molecular skeleton of straight chain, ring-type or side chain, has alternatively side group.
Therefore, realize trifunctional monomer and Organohalogen compounds segment (for example, poly-fluorine organic group) or the not connection of organic segment of halogenation by the covalency means, relate to and the one or more functional groups formation key that is positioned on each group.The example that can be used for the chemical reaction functional group of this purpose includes but not limited to amino, hydroxyl, sulfydryl, carboxyl, carbonyl, carbohydrate group, adjacent glycols (vicinal diols), thioether class, 2-alkamine, 2-amineothiot class, guanidine radicals, imidazolyl and phenolic group group.
Can (for example realize trifunctional monomer and Organohalogen compounds segment with joint, poly-fluorine organic group) or non-halogenated organic group covalently bound, this joint comprises the reactive moieties that can react with this class functional group that exists in trifunctional monomer and Organohalogen compounds segment or non-halogenated organic segment.For example, the oh group of trifunctional monomer can with the carboxyl of joint, or the derivative of its activation reacts, and causes forming a kind of ester that connects the two.
The example of the part that can react with mercapto groups comprises type XCH 2CO-(is X=Br, Cl or I wherein) the alpha-halogen acetyl compounds; this compound exhibits is specifically reactive for mercapto groups; but it can also be used for modified imidazole base, thioether, phenol and amino group (such as Gurd, Methods Enzymol.11:532 (1967) is described).The N-maleimide derivatives also is considered to have selectivity for mercapto groups, but can additionally be used for being coupled to amino group under certain conditions.If connect by forming disulphide bridges, these reagent (2-imino-sulfane (2-iminothiolane) (Traut et al. for example then, Biochemistry 12:3266 (1973)), it introduces thiol group by transforming amino group) can think sulfhydryl reagent.
The example of the reactive moieties that can react with amino group comprises for example alkylation and acylting agent.Representational alkylating reagent comprises:
(i) there is not this compound exhibits under the reactive thiol group in alpha-halogen acetyl compounds for the specificity of amino group and is having type XCH 2CO-(is X=Cl, Br or I wherein) (for example, described such as Wong Biochemistry 24:5337 (1979)); (ii) N-maleimide derivatives class, these derivatives can also or by acylation reaction and the amino group that adds on the cyclocarbonyl group (for example react by the reaction of Michael type, such as Smyth et al., J.Am.Chem.Soc.82:4600 (1960) and Biochem.J.91:589 (1964) are described); (iii) aryl halide class, for example reactive nitro halogenated aromatic compound class; (iv) alkyl halide class (for example such as McKenzie et al., J.Protein Chem.7:581 (1988) is described); (v) can form with amino group aldehydes and the ketone of schiff bases, thus run through adducts that reduction reaction forms normally stable provide stable amine; (vi) for example Epicholorohydrin and bisoxirane of epoxide derivate class, these derivatives can with amino, sulfydryl or phenolic hydroxyl group radical reaction; (the vii) chloride derivatives class of s-triazine, for example amino, sulfydryl and oh group have reactivity to these derivatives very much for nucleophile; (viii) based on the aziridines (for example such as Ross, J.Adv.Cancer Res.2:1 (1954) is described) of the s-triaizine compounds that describes in detail above, by ring opening they and nucleophile for example amino group react; (ix) square diethyl phthalate (squaric acid diethyl esters) (such as Tietze, Chem.Ber.124:1215 (1991) is described); And (x) α-alkylhalide group ethers, they are to have more reactive alkylating agent (such as Benneche et al., Eur.J.Med.Chem.28:463 (1993) is described) than normal alkyl halide owing to the activation that causes by ether oxygen atom.
Representative amino-reactive acylting agent comprises: (i) isocyanates and isosulfocyanate, and aromatic derivant class particularly, they form stable urea and thiourea derivative class accordingly; (ii) SULPHURYL CHLORIDE class, by Herzig et al., Biopolymers 2:349 (1964) describes for they; (iii) chloride of acid class; (iv) for example nitrophenyl ester class or N-hydroxy-succinamide ester class of active ester class; (v) anhydrides is for example mixed, symmetrical, or N-carboxylic acid class; (vi) be used for other useful reagent that amido linkage forms, for example such as M.Bodansky, Principles of Peptide Synthesis, Springer-Verlag, 1984 is described; (vii) acid azide class, for example wherein this azido group is to use Sodium Nitrite to be produced by preformed hydrazide derivatives, such as Wetz et al., Anal.Biochem.58:347 (1974) is described; And (viii) imide ester class, they form stable amidine class when reacting with amino group, and for example such as Hunter and Ludwig, J.Am.Chem.Soc.84:3491 (1962) is described.Form the Schiff bases thereby aldehydes and ketone and amine are reacted, can advantageously make these alkali stable by the reductive amination effect.Thereby alkoxy amino partly is easy to react with ketone and aldehydes and produces stable alcoxyl amine, and for example such as Webb et al., in Bioconjugate Chem.1:96 (1990) is described.
Can comprise diazonium compound class for example diazonium acetate class and diazoacetamide class with the example of the reactive moieties of carboxylic group reaction, thereby they produce ester group with the high specific reaction, for example such as Herriot, Adv.Protein Chem.3:169 (1947) is described.Can also use carboxy-modified dose of for example carbodiimide class, and then they form amido linkage by formation O-acylurea and react.
Should be understood that, if desired before the reaction trifunctional monomer and Organohalogen compounds segment or not the functional group in the organic segment of halogenation can change into other functional groups, for example be used for providing other reactivity or selectivity.The example that is used for the method for this purpose comprise use reagent for example the dicarboxylic anhydride class amine is changed into carboxyl; For example N-ethanoyl homocysteine thiolactone, S-ethanoyl mercaptosuccinic acid acid anhydride, 2-imino-sulfane (2-iminothiolane) or the succinimide derivatives class that comprises thiol group change into thio-alcohol with amine to use reagent; Use reagent for example alpha-halogen acetic ester changes into the carboxyl class with thio-alcohol; For example ethyleneimine or 2-bromine ethamine change into amine with thio-alcohol to use reagent; And then use reagent for example carbodiimide class change into amine with Diamines with the carboxyl class; And use reagent for example toluene sulfonyl chloride (tosyl chloride) and then carry out transesterification reaction and be hydrolyzed into mercaptan with sodium acetate alcohols is changed into thio-alcohol with thioacetate.
If desired, can so-called distance of zero mark degree joint used according to the invention (relate to the direct covalent attachment of organic segment of the reactive chemical group of trifunctional monomer and Organohalogen compounds segment or not halogenation, and do not introduce other connection material).Yet, the most common ground, this joint can comprise two or more aforesaid reactive moieties that connect by spacer elements.Particular functional group in that the existence of this class spacer allows bifunctional linker and reflunomide and body or the charged groups reacts, and causes covalently bound between the two.These reactive moieties can be identical (homology bifunctional linker) or different (allos bifunctional linker in the joint, maybe when having several dissimilar reactive moieties, the multifunctional joint of allos), multiple potential reagent is provided, and these potential reagent can bring organic segment of this trifunctional monomer and not halogenation or the covalency between the insoluble segment of water attached.
Spacer elements in joint typically is comprised of straight or branched, and can comprise C 1-10Assorted alkyl, the C of alkyl, 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems, Huo – (CH of aryl, 3 to 10 atoms 2CH 2O) nCH 2CH 2-, wherein n is 1 to 4.
Biologically active agent
Coating of the present invention comprises one or more biologically active agents.Can be by (for example making the self-assembled coating component, the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water) and biologically active agent is admixed together and before implanting this mixture is applied (coating) realizes combination to article surface.In certain embodiments, this biologically active agent covalently be connect or be complexed in this self-assembled coating oligomer compounds (for example, the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water), preferably on branch's compound.At U.S. Patent number 6,770,725 and U.S. Patent Publication No. 20070037891 in how provide can covalently be to connect or be complexed to detailed description on the oligomeric oligopolymer of fluoridizing biologically active agent, they each is combined in this by reference.The biologically active agent that can be used for method of the present invention and composition comprises therapeutical agent, diagnostic reagent and prevention reagent.They can be the compound of natural generation (existence), synthetic organic compound or mineral compound.The biologically active agent that can be used for method of the present invention and composition includes but not limited to protein, the peptide class, carbohydrate, antibiotics, the antiproliferative class, the rapamycin Macrolide, the anodyne class, the narcotic class, the anti-angiogenic agent class, the vasoactive agent class, the antithrombotics class, the immunomodulator class, the cytotoxic agent class, the antiviral agent class, the antithrombotic agent medicine, for example terbrogrel and Ramatroban, antibody class, neurotransmitter, the psychoactive drug class, oligonucleotides, protein, lipid, and any biologically active agent described herein.
Exemplary therapeutical agent comprises tethelin, for example human growth hormone, thyrocalcitonin, rHuGM-CSF (GMCSF), ciliary neurotrophic factor and parathyroid hormone.Other specific treatment agent comprise parathyroid hormone-related peptide, somatostatin, testosterone, progesterone, estradiol, Nicotine, fentanyl, Norethisterone, clonidine, Scopolamine, salicylate, Salmeterol, formoterol, salbutamol (salbutamol, albeterol), diazepam (valium), heparin, dermatan, siderochrome A(ferrochrome A), short erythrocyte auxins, diethylstilbestrol, leuprorelin acetate (Acetate, lupron), the oestrogenic hormon estradiol, male sex hormone halo testis albumen (androgen halotestin), 6-thioguanine, Ismipur, Zoladex (zolodex), taxol, lisinopril/Zestril, streptokinase, aminobutyric acid, the hemostatic agent hexosamine, bromocriptine methanesulfonate sheet (parlodel), tacrine, potassium paraaminobenzoate (potassium amide powder, potaba), metamfetamine (adipex), memboral, phenylethyl barbituric acid, Regular Insulin, gamma globulin, azathioprine, papoid (papein), acetaminophen, Ibuprofen BP/EP, acetylsalicylic acid, suprarenin, flucloronide (flucloronide), Percocet (oxycodone percoset), Wy-16225 (dalgan), phreniline butabital, PROCAINE HCL, PHARMA GRADE, Novocaine, morphine, oxycodone, aloxiprin, Bromfenac (brofenac), Ketoprofen, ketorolac, protohemine, vitamin B-12, folic acid, magnesium salts, vitamins D, vitamins C, vitamin-E, vitamin A, Vitamin U, vitamin(e) L, vitamin K, pantothenic acid, the aminophenyl butyric acid, penicillin, acyclovir, Ofloxacine USP 23 (oflaxacin), the amoxycilline Trihydrate bp, tobramycin, retrovior, lamivudine (epivir), nevirapine, gentamicin, S 578 (duracef), amphotericin (ablecet), butoxycaine, oxybuprocainum, benzilic acid 6-methoxytropine ester, Diponium Bromide salt (spaston salt, diponium salts), butyl .beta.-piperidinohydrocinnamate, atropyltropeine, feclemine, leiopyrrole, octamylamine, Oxybutynin, salbutamol, Orciprenaline (metaproterenol), the beclometasone dipropionate, the triamcinolone ethanamide, the budesonide acetonide, ipratropium bromide, flunisolide, Sodium Cromoglicate (cromolyn sodium), Exmigra, and albumen or peptide medicine class for example TNF antagonist class or interleukin antagonist class.For example, this biologically active agent can be anti-inflammatory agent, for example NSAID, reflunomide or cox 2 inhibitor, for example rofecoxib, celecoxib, valdecoxib or Prexige.
Exemplary diagnostic reagent comprises the preparation class, for example is used for those of positron emission tomography (PET), computed assisted tomography (CAT), SPECT (single photon emission computed tomography), X-ray, fluorescent microscopy and nuclear magnetic resonance (MRI).The suitable material that is used as contrast medium in MRI comprises the gadolinium chelate compound class, and iron, magnesium, manganese, copper and chromium complex.The example that is used for CAT and X-ray material comprises iodo (iodine class) material.
Preferred biologically active agent is basically pure peptide or albumen.Albumen is normally defined by 100 or more amino-acid residue and forms; Peptide is less than 100 amino acid whose residues.Unless otherwise indicated, as used herein, term albumen is finger protein and peptide.For example can pass through to separate from natural origin, recombination form, or lay eggs white synthetic next life by peptide.These examples comprise growth hormones, for example human growth hormone and Trobest; Enzyme, for example DNase(DNA enzyme), protease, urico-oxidase, Unidasa (alronidase), alpha-galactosidase and alpha-glucosidase; Antibody class, for example Herceptin.
The rapamycin Macrolide
Rapamycin (sirolimus) is a kind of immunosuppression lactam macrolide of producing by streptomyces hygroscopicus (Streptomyces hygroscopicu).Referring to for example McAlpine, J.B., et al., J.Antibiotics 44:688 (1991); Schreiber, S.L., et al., J.Am.Chem.Soc.113:7433 (1991); And U.S. Patent number 3,929,992, be combined in by reference this.The exemplary rapamycin Macrolide that can be used for the inventive method and composition includes but not limited to rapamycin, CCI-779, everolimus (being also referred to as RAD001) and ABT-578.CCI-779 is at U.S. Patent number 5,362, the ester (the 42-ester with 3-hydroxyl-2-methylol-2 Methylpropionic acid) of a kind of rapamycin that discloses in 718.Everolimus is at U.S. Patent number 5,665, a kind of alkylating rapamycin that discloses in 772,40-O-(2-hydroxyethyl)-rapamycin.
The antiproliferative class
The exemplary antiproliferative that can be used for the inventive method and composition includes but not limited to mustargen, endoxan, ifosfamide (iosfamide), melphalan, Chlorambucil, uracil mustard, Emcyt, ametycin, AZQ, phosphinothioylidynetrisaziridine, busulfan, hepsulfam, carmustine, lomustine, semustine, streptozotocin, Dacarbazine, cis-platinum, carboplatin, Procarbazine, methotrexate, trimetrexate, Fluracil, floxuridine, cytosine arabinoside, fludarabine, capecitabine, azacitidine, Tioguanine, mercaptopurine, A Luopulin (allopurine), CldAdo, gemcitabine, pentostatin, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol (taxol), Docetaxel (docetaxel), daunorubicin, Dx, gengshengmeisu, idarubicin, primycin (Plicamycin, plicamycin), mitomycin, amsacrine, bleomycin, aminoglutethimide, Anastrozole, finasteride, KETOKONAZOL, tamoxifen, flutamide, Leuprolide, goserelin, Gleevec TM(Novartis), leflunomide (Pharmacia), SU5416(Pharmacia), SU6668(Pharmacia), PTK787(Novartis), Iressa TM(AstraZeneca), Tarceva TM(Oncogene Science), Herceptin (Genentech), Erbitux TM(ImClone), PKI166(Novartis), GW2016(GlaxoSmithKline), EKB-509(Wyeth), EKB-569(Wyeth), MDX-H210(Medarex), 2C4(Genentech), MDX-447(Medarex), ABX-EGF(Abgenix), CI-1033(Pfizer), Avastin TM(Genentech), IMC-1C11(ImClone), ZD4190(AstraZeneca), ZD6474(AstraZeneca), CEP-701(Cephalon), CEP-751(Cephalon), MLN518(Millenium), PKC412(Novartis), 13-cis-vitamin A acid (retinoids, 13-cis-retinoic acid), isotretinoin, retinyl palmitate, 4-(hydroxyl carboxyphenyl)-VAAE (4-(hydroxycarbophenyl) retinamide), Misonidazole, nitre ammonia the third acridine, mitoxantrone, hydroxyurea, L-ASP, interferon alpha, AP23573, Cerivastatin, troglitazone, the CRx-026DHA-taxol, Taxoprexin, TPI-287, the lipid of sphingosine base (based on the lipid of sphingosine, Sphingosine-based lipids), and mitotane.
Cortical steroid
The exemplary cortical steroid that can be used for the inventive method and composition includes but not limited to the 21-prebediolone acetate, Modrasone, alphasone, amcinonide, beclometasone, Betamethasone Valerate, celestone-V, budesonide, Chloroprednisonum, clobetasol, clobetasol propionate, clobetasone, CB, clocortolone, Syntestan, Kendall compound, cortisone, cortivazol Azacort (deflazacon), Hydroxyprednisolone Acetonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difluprednate, glycyrrhetinic acid, Fluazacort, flucloronide, fluorine compound, flumethasone pivalate, flunisolide, fluocinolone acetonide acetonide (Flucinoloni Acetonid, flucinolone acetonide), fluocinonide, fluocinolone acetonide, fluocortin (fluocortin butyl, fluocortin butyl), fluocortolone (fluocortolone), fluocortolone hexanoate (fluorocortolone hexanoate), nerisona, fluorometholone, P-1742, StL-1106, fluprednisolone, (fluorine hydrogen can be relaxed and comfortable, flurandenolide) for flurandrenolide, formocortal, halcinonidedcorten, halometasone, halopredone acetate, hydrocortamate, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, HP, hydrocortisone 21-sodium succinate (hydrocortisone 21-sodium succinate), uncle's d ritalinic acid hydrocortisone (hydrocortisone tebutate), mazipredone, Zpoflogin, meprednisone, methylprednisolone (methylprednicolone), furoic acid momisone, paramethasone, prednicarbate, prednisolone, prednisolone 21-diethyl amino yl acetate (prednisolone21-diedryaminoacetate), prednisolone phosphate sodium, prednisolone bisuccinate, the meta-sodium sulfo benzoate of prednisolone 21-, stearic (acid) the basic hydroxyethanoic acid sodium (prednisolone sodium 21-stearoglycolate) of prednisolone 21-, prednisolone 21-tertbutylacetate, 21-front three acetyl Ultracortene-H, prednisone, W-4869 (prednival), prednylidene, methylene prednisolone 21-diethylamino ethyl ester, tixocortol, triamcinolone, Triamcinolone Acetonide, triamcinolone benetonide and triamcinolone hexacetonide.Cortical steroid with structurally associated of similar anti-inflammatory characteristic also is intended to be included in this group.
The NSAID(nonsteroidal anti-inflammatory drug)
Exemplary non-steroidal (steroid) anti-inflammatory drug (NSAID) that can be used for the inventive method and composition includes but not limited to naproxen sodium, diclofenac sodium, Potassium diclofenac, acetylsalicylic acid, sulindac, diflunisal, piroxicam, indomethacin, Ibuprofen BP/EP, nabumetone, choline magnesium trisalicylate, sodium salicylate, Sasapyrin (salsalate), fenoprofen, flurbiprofen, Ketoprofen, Meclofenamate Sodium, meloxicam, Taisho), sulindac, and tolmetin.
The anodyne class
The exemplary anodyne class that can be used for the inventive method and composition includes but not limited to morphine, morphine monomethyl ether, heroine, Ethylmorphine, O-carboxymethyl morphine, O-acetylmorphine, hydrocodone, hydromorphone, oxymorphone, oxycodone, dihydrocodeine, thebaine, metopon, etorphine (ethorphine), racecadotril, Diprenorphine, buprenorphine, phenomorphan, levorphanol, ethoheptazine, ketobemidone, Dihydroetorphine and dihydro racecadotril.
The antiseptic-germicide class
The exemplary antiseptic-germicide that can be used for the inventive method and composition includes but not limited to penicillin G, penicillin v, the X-1497, Oxazacillin, cloxacillin, dicloxacillin, nafcillin, the Ampicillin Trihydrate, the amoxycilline Trihydrate bp, Gepcillin, ticarcillin, the mezlocillin, piperacillin, the azlocillin, temocillin, cefoxitin (cepalothin), Cephapirin, Cephradine, Cephaloridine, Cephazolin, Cefamandole, cephalofruxin, Cephalexin Monohydrate Micro/Compacted, Prozef, cefaclor, Loracarbef, cefoxitin, cefmetazole (cefmatozole), cefotaxime, ceftizoxime, ceftriaxone, cefoperazone, ceftazime, Cefixime Micronized, Cefpodoxime, Ceftibuten, Cefdinir, cefpirome, cefepime, BAL5788, BAL9141, imipenum, ertapenem, meropenem, aztreonam (astreonam), Clavulanate, Sulbactam, tazobactam, Streptomycin sulphate, Liu Suanyan NEOMYCIN SULPHATE, kantlex, paromycin (paromycin), gentamicin, tobramycin, amikacin, netilmicin, spectinomycin, sisomicin, dibekacin (dibekalin), isepamicin, tsiklomitsin, Uromycin (duomycin), Demethylchlortetracycline, Minocycline HCl, terramycin, methacycline, Vibravenos, erythromycin, Azythromycin, clarithromycin, Ketek, ABT-773, lincomycin, clindamycin, vancomycin, oritavancin, Da Beiwan star (dalbavancin), teicoplanin, Quinupristin and dalfopristin, sulfanilamide (SN), para-amino benzoic acid, Sulphadiazine Sodium, Sulfafurazole, Sulfamethoxazole, phthalylsulfathiazole, Linezolid, Nalidixic Acid, oxolinic acid, norfloxicin, Pelox, enoxacin, Ofloxacine USP 23, Ciprofloxacin, temafloxacin, lomefloxacin, fleroxacin, grepafloxacin, Sparfloxacin, trovafloxacin, Clinafloxacin, Gatifloxacin, Moxifloxacin, gemifloxacin, Sitafloxacin, metronidazole, daptomycin, T-3811, ramoplanin, Faropenem, polymyxin, tigecycline, AZD2563, and trimethoprim.
The local anesthetic class
The exemplary local anesthetic class that can be used for the inventive method and composition includes but not limited to Cocaine, PROCAINE HCL, PHARMA GRADE, lignocaine, prilocaine, mepivacaine, bupivacaine, articaine, tetracaine, chloroprocaine, etidocaine and ropivacaine (ropavacaine).
The antispasmodic class
The exemplary antispasmodic class that can be used for the inventive method and composition includes but not limited to coromegine, belladonna, bentrl hydrothloride preparation (bentyl), tropine preparation (cystospaz), tolterodine preparation (detrol) (tolterodine), Dicycloverine, Oxybutynin, donnatol(Tropintran another name), donnazyme(Tropintran another name), fasudil, cyclobenzaprine (flexeril), Glycopyrronium Bromide, tropine melate, tropine, hyoscyamine sulfate (levsin), levsinex(tropine another name), Librax (librax), homapin (malcotran), Ritalin (novartin), oxyphencyclimine, Oxybutynin, hyoscine methobromide alkali preparation (pamine), tolterodine, tiquizium bromide (tiquizium), prozapine, and Pinaverium Bromide.
Coating
Coating of the present invention can be designed to by changing the oligopolymer size, their solubleness in Physiological Medium, and/or with helping oligopolymer with this coating surface interaction placed on it to change adhesive power with the surface.The interaction that this class is favourable can comprise for example coordination (being that carboxylate group is coordinated on the metallic surface), and/or the hydrogen bond between these oligopolymer and equipment surface.In certain embodiments, thus this self-assembled coating is applied on the surface of implantable medical supply and forms a shallow layer (that is, 0.5-50.0 micron thickness).Because coating of the present invention does not have the characteristic of base polymer, (for example, curling and stent) their incrust or crackings during this equipment of physical operations.Before coating is broken (for example, by the coating distortion, or by coating is exposed to energy source) by the rate of diffusion of restriction reagent from self-assembled coating, coating of the present invention can be controlled the release that is combined in the biologically active agent in this self-assembled coating.
The major function of this type coating can be to increase the efficient that the local delivery biologically active agent continues the time durations of restriction.This self-assembled coating alternatively with the biologically active agent complexing, or covalency system connects, or physical bond, or is applied in the mixture that comprises biologically active agent.The quantity that is loaded into the biologically active agent in this self-assembled coating will depend on the partial concn of hope and the graphic representation that discharges from self-assembled coating.
In some embodiments, coating of the present invention comprises the insoluble segment of water (segment of for example, fluoridizing) of the surperficial fluorine factor that hope is provided.This fluoridizes part as working for the shield that is combined in the biological reagent in this self-assembled coating, avoids and the undesirable interaction of Physiological Medium (for example, fluid and blood constitutent).This permission is transferred to the effective dose of this promoting agent on the target site by the limited transfer of delivery platform.As the described herein, this biologically active agent can by hydrolyzable joint covalently be attached in the self-assembled coating the oligomer compound (for example, the oligomeric oligopolymer of fluoridizing (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water), preferably on branch's compound.In these embodiments, the hydrolysis that should be understood that joint also can occur in this self-assembled coating or after this biologically active agent slave unit surface diffusion.It is desirable to limit near the hydrolytic deterioration of implant site to avoid changing partly pH and generation inflammatory by-products.
Coating of the present invention can put on the surface of medical supply in any amount of mode, include but not limited to this self-assembled coating material of galvanic deposit from solution or suspension, dipping, spraying, scratch brushing, printing or spin coating, if necessary solvent removal step and then.Can find in an embodiment and can how make and use further specifying of these coatings.
Can be by in solution, with solid or form of suspension in conjunction with these components, one or more oligomer compounds (for example the oligomeric oligopolymer of fluoridizing (such as side chain or the oligomeric oligopolymer of fluoridizing of straight chain) or comprise the branched compound of the insoluble segment of water), preferably branch's compound, and biologically active agent forms this self-assembled coating.This self-assembled coating can be applied on the surface of medical supply, and then solvent removal step (if necessary).Alternately, coating ingredients can be with the layering form (for example, the oligomeric oligopolymer of fluoridizing (such as side chain or the oligomeric oligopolymer of fluoridizing of straight chain)) applies maybe and the branch's compound that comprises the insoluble segment of water can be applied on the surface of medical supply, as stratum basale, and then biologically active agent as top layer (for example these one or more biologically active agents can with the oligomeric compound of branch for example the oligomeric oligopolymer of fluoridizing combine), or the oligomeric oligopolymer of fluoridizing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise branch's compound of the insoluble segment of water, preferably the oligomeric compound of branch can be applied on the medical supply surface as Topcoating, encapsulate the stratum basale (for example, can or comprise that with the oligomeric oligopolymer of fluoridizing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) branch's Compound Phase of the insoluble segment of water is combined) of one or more biologically active agents).Can apply a plurality of alternating layers as required.Alternatively, self-assembled coating of the present invention can comprise that the cofactor tackiness agent is used for improving on the components composition that this self-assembled coating is attached to this equipment surface or this self-assembled coating.Can be by with the oligomeric oligopolymer of fluoridizing (for example, and be applied on the surface of medical supply the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise that branch's compound, cofactor tackiness agent and one or more biologically active agents of the insoluble segment of water mix to form these coatings.Can be by branch's compound of applying the oligomeric oligopolymer of fluoridizing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprising the insoluble segment of water as stratum basale, and then biologically active agent forms this type coating as top layer with cofactor binder layer (or vice versa) placed in the middle.The cofactor tackiness agent that can be used for coating of the present invention includes but not limited to carbowax, gelatin, albumin glue, dextrose, salt compounded of iodine, polysaccharide, lipid, nucleic acid, PEG, Sodium Citrate, Si Liaodengji dicalcium phosphate feed grade, lactose, sucrose, glucose, N.F,USP MANNITOL, silicic acid, carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, gum arabic (acacia), glycerine, agar, paraffin, general stream Buddhist nun restrains gel (pluronic gel), glyceryl monostearate, kaolin, calcium stearate/magnesium, the solid polyethylene glycol class, Sulfuric acid,monododecyl ester, sodium salt, and propylene glycol.
Self-assembled coating of the present invention can also be applied directly on the pending tissue surface.When directly applying, the component of this coating can mix and be applied on the handled surface.Make in this way, (for example it is desirable to the oligomer compound that to drain, the oligomeric oligopolymer of fluoridizing (such as side chain or the oligomeric oligopolymer of fluoridizing of straight chain) or comprise branch's compound of the insoluble segment of water), preferably branch's compound is used for self-assembled coating.
The medical supply that applies
Can apply extensive various implantable medical supply with the compositions and methods of the invention is used for improving their biocompatibility and is used for biologically active agent is delivered to the treatment site of hope.These medical supplies can comprise temporary medical supply, not equipment, non-vascular type equipment, transcutaneous device and the epidermis equipment of implantable vessel.Transcutaneous device comprises the article of skin permeation, extends in the body from external thus.Epidermis equipment uses at epidermis.Transcutaneous device comprises the kind of transdermal, enter in the body from external expansion thus, be not limited to dissimilar conduit, balloon catheter, the neurone guide catheter, the neurone microtubular, the neurone microfilament, the neurone air bag, the coronary artery silk, the coronary artery guide catheter, stent graft, stent delivery system, the coronary artery seal wire, the coronary artery guide catheter, the intubator sheath, spreader, seal wire, syringe needle, dialysis sheath intubate, strainer, liquid discharge pipe is ductus thoracicus for example, operation instrument is tweezers for example, traction apparatus, syringe needle, and catheter sheath (catheter cuff).
Temporary medical supply of the present invention can comprise that multiple kinds of energy source (comprising the ultrasonic energy, thermal energy source, electromagnetic-energy and/or the vibration energy) is used for destroying this self-assembled coating and discharging this biologically active agent.For example, can use to have frequency in 20kHz to 100MH scope, preferably in 0.1MHz to 20MHz scope, and strength level is from 0.05W/cm 2To 10W/cm 2Scope in, preferably from 0.5W/cm 2To 5W/cm 2Scope in ultrasonic extra power.This ultrasonic energy can be oriented on this self-assembled coating and also or pulsedly apply continuously and continue from 5 seconds to 30 minutes in the scope, preferably the time durations in the scope from 1 minute to 15 minutes.Alternately, the surface temperature of this temporary medical supply can be heated (for example, in the scope from 36 ℃ to 48 ° of C) thereby, vibration or stand electromagnetic energy and help biologically active agent to discharge in position and the time of hope.
In another method, (for example, expansion equipment) this self-assembled coating is mechanically destroyed when this equipment surface distortion.For example, but temporary medical supply of the present invention can comprise the section (sections) of radial expansion, this section (sections) can become radial dilatation from the minor diameter transformation of configuration, and normally cylindrical configuration can realize this configuration when this expandable structure is positioned at the target site of hope.This expandable structure can have the elasticity of minimum degree, and therefore ductility for example need to apply that external force is extended and it is fixed on the target site place.Typically, this expansion force can be provided from expansion structure by air bag or another kind.Be used for extendible temporary medical supply of the present invention and can use resilient material, the alloy of for example stainless steel of tempering, or super-elastic property is Nitinol for example TMAlloy, and form main part (main paragraph, body segment) thus so that when it is unrestricted (, discharge from the radial constraint power of sheath) it can have the radially diameter of extension of its hope.Should be can be with its radial constraint configuration tracked and send (for example, by this expandable structure is placed in delivery sheath or the pipe, and removing sheath at the target site place) from expansible structure of expansion.The size of this expandable structure will depend on the use position of its expection.Typically, the length in this expandable structure can have from about 5mm to about 100mm scope for vascular applications is normally from about 8mm to about 50mm.Under expanded configuration not, be used for the diameter of the cylindrical expandable structure of vascular applications, scope is from about 0.5mm to about 10mm usually, more generally from about 0.8mm to about 8mm; Under expanded configuration, this diameter range is from about 1mm to about 100mm, preferably from about 2.0mm to about 30mm.This expandable structure can have usually from about 0.025mm to 2.0mm, the thickness in preferably from about 0.05mm to about 0.5mm scope.
Medicament elution air bag (DEB)
Vascular obstruction disease is mainly changed by the vascular system physiopathology and causes, has caused thickening from the blood vessel lining of fatty deposits or patch.The most frequently used therapeutic modality that is used for vascular obstruction disease is operation the method for bypass.Yet as substituting or feasible pattern for the treatment of, the interior intervention of blood vessel gains public acceptance and puts into practice.Balloon angioplasty is designed to expand occluding vascular based on airbag aeration, and the compression patch, thereby allow perfusion illing tissue.In in most of blood vessels, intervening, guide cannula is advanced in the patient's vascular until the distal tip of this guide cannula be positioned at target location near.The distal end of seal wire being released this guide cannula enters into patient's blood vessel, until the distal end of this seal wire is crossed (dilated) damage (lesion) that remains to be expanded.To be advanced in the patient's blood vessel at the dilating catheter that its distal part has an inflatable bladders and cross this damage through the seal wire of introducing previously until the air bag of this dilating catheter is correctly located.The success of intervening in the blood vessel is usually higher, but because near the restenosis initial damage has reduced vascular patency (patency) usually, causes the again obstruction of blood vessel.Providing a kind of method from the ability of balloon surface local delivery medicine aspect the control restenosis.Can apply with the medicine of hope all or in part exterior airbag surface, can also control the time of airbag inflation or the diversity of expansion, so that the height that this " medicament elution air bag " becomes for localized drug delivery adapts to and firm instrument
The compositions and methods of the invention can be used for the different application of medicament elution airbag technology, for example through skin stride lumen angioplasty (percutaneous translumenal angioplasty) (PTA), coronary angioplasty (PTCA), neural blood vessel plasty (PTNA), air bag aortic valve film angioplasty (balloon aortic valvuplasty) (BAV).In addition, composition of the present invention allows in conjunction with different biological reagents, and this depends on the application of these medicament elution air bags.
In an application, DEB can also be used for repairing because the narrow aortic valve of calcium accumulation (calcium buildup) hardening as air bag aorta vessel valvuloplasty.This air bag inserted and inflation enters and is used in this aortic valve increasing the open size of valve and improving volume of blood flow.Traditional air bag aortic valve film angioplasty fails to stop the restenosis in the patient body many times.Thereby the medicament elution air bag allows to be used for wash-out in conjunction with anti-recoarctation of aorta medicine and enters restenosis after preventing from treating in the aortic valve of expansion in this case.
In Another application, can treat by the untreatable peripheral diseases of support with DEB.For blood vessel is especially true below knee, wherein these blood vessels are less and rupture at torque lower bracket pillar.
A kind of possible non-vascular applications of medicament elution air bag is the topochemistry treatment.Balloon catheter can be coated with carcinostatic agent and be incorporated in the cancerous tissue.
The air bag that is used for angioplasty classifies as high-pressure gasbag.The standard air bag is comprised of a cylindrical body, two conical centrums and two necks.Can use and characteristics customize special angle and the shape of air bag according to physiology.In other zones (for example esophagus, bile duct, urethra, uterine tube, heart valve, lacrimal and carpel channel expansion), high-pressure gasbag also is used for expanding a plurality of contractions and obstruction.Other application that are used for high-pressure gasbag comprise that location, obstruction, light treatment (phototherapy), heat shift and the interior graft of blood vessel is sent.
High-pressure gasbag is made (only extending 5-10%) by non-conformability or Low compliance material, and these materials have controlled size and dimension.These air bags of thin-walled are presented at tensile strength higher under the lower prolongation.The most high-pressure gasbag is made by PET or nylon.Has higher tensile strength at maximum rated pressure P ET.It can be molded as and have diameter from the ultra-thin outer wall (5-50mm) of 0.5-50mm.Nylon be softer and easily refolding enter into guide catheter in order to more easily extract out.Bi-material has all proved and oilness, abrasive action is provided and has pierced through the coating of other features such as tolerance, electroconductibility, thrombus generative nature (thrombogenicity), drug release and reflectivity compatible.
The rated pressure that is used for angioplasty is 2-20atm.Larger-diameter air bag has low rated pressure because the stress in the airbag wall increases when expanding into specific diameter.The PTCA balloon catheter has the 2-4mm diameter usually, 10-40mm length and the rated pressure with 10-20atm.The PTA balloon catheter usually has 4-14mm diameter and 20-200mm length and has the rated pressure of 8-20atm.
Preparation
Can be with the oligomeric oligopolymer of fluoridizing of the present invention (for example, the oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise the branched compound of the insoluble segment of water, preferably branched compound, and biologically active agent is mixed with homogeneous phase solid or solution, Solution Dispersion body (single-phase or heterogeneous).This biologically active agent and the oligomeric oligopolymer of fluoridizing (for example oligomeric oligopolymer of fluoridizing of side chain or straight chain) or comprise the conformational array (conformational arrangement) of branch's compound of the insoluble segment of water and consistency can instruct based on release profiles and solubleness enhancement the curative effect of preparation.
Propose following examples thereby complete disclosure and the explanation that how to realize, make and be evaluated at this claimed method and compound is provided for those of ordinary skills, and be intended to only not to be used for as of the present invention illustrating to limit the scope of their patent that ladies and gentlemen contriver thinks.
Acronym
Following acronym refers to the compound listed.
BAL gathers (difluoro methylene), α-fluoro-ω-(2-hydroxyethyl)
CDCl 3Deuterochloroform
The DBDL dibutyl tin laurate
The DCM methylene dichloride
The DIC DIC
The DMAc N,N-DIMETHYLACETAMIDE
DMAP 4-(dimethylamino) pyridine
The DMF dimethyl formamide
The DMSO dimethyl sulfoxide (DMSO)
EtO oxyethane
HCl hydrochloric acid
The KBr Potassium Bromide
The Methionin of KD dansyl mark (dansyl labelled lysine)
The LDI lysinediisocyanate
MeOH methyl alcohol
NaOH sodium hydroxide
N2 nitrogen
The PBS phosphate buffer soln
The PCL polycaprolactone
PTMO polytetramethylene oxide compound
PTX taxol (taxol)
The SA Whitfield's ointment
The TEA triethylamine
The THF tetrahydrofuran (THF)
The meta-tetramethylxylene diisocyanate of TMX (vulcabond)
Embodiment
Embodiment 1: the synthetic and sign oligomeric fluoroester of compound 1().
At N 2Lower, in the presence of DBDL catalyzer under 70 ° of C, at DMAc(80mL) in make PTMO(15.0g, 14mmol) and LDI(5.9g, 28mmol) reacted 2 hours.Perfluor alcohol (13.15g, 31mmol) is dissolved in DMAc(25mL) in, add in the reaction, and at N 2Lower at room temperature the stirring spent the night.By solvent extraction and kation S PE(Solid-Phase Extraction) product (compound 1) is carried out purifying.The GPC(gel permeation chromatography) (diox moving phase): retention time 25 minutes. 1H NMR (400MHz, CDCl 3) δ (ppm) 4.24-4.46 (CH 2-O, BAL), 3.94-4.13 (CH 2-O-CO, PTMO), 3.74 (CH 3, LDI), 3.28-3.50 (CH 2-O, PTMO), 2.98-3.28 (C H 2-NH, LDI), 2.29-2.60 (CH 2-CF 2-, BAL), 1.16-1.96 (PTMO and LDI CH 2).IR analyzes consistent with chemical structure: 3318cm -1(N-H) H-combination, 2930cm -1(C-H), 2848cm -1(C-H), 1712cm -1(C=O) urethane acid amides, 1524cm -1(C-N), 1438cm -1(C-N), 1356cm -1(C-O), 1400-1000cm -1(C-F).Ultimate analysis: 20%F.Dsc analysis: T g=-69 ° of C.By being dissolved among the MeOH and using 1000MWCO RCF regenerated cellulose film dialysis three days that compound 1 is further purified.
Embodiment 2: the synthetic and sign oligomeric fluoro-acid of compound 2().
Compound 1 is dissolved among the MeOH and with 1N NaOH processes.Product (compound 2) neutralizes with 1N HCl, is deposited in the water, and dry.GPC(diox moving phase): retention time 25 minutes. 1H NMR (400MHz, CDCl 3) δ (ppm) 4.26-4.48 (CH 2-O, BAL), 3.96-4.23 (CH 2-O-CO, PTMO), 3.30-3.52 (CH 2-O, PTMO), 3.07-3.22 (C H 2-NH, LDI), 2.36-2.55 (CH 2-CF 2-, BAL), 1.14-1.94 (PTMO and LDICH 2).IR analyzes consistent with chemical structure: 3318cm -1(N-H) H-combination, 2930cm -1(C-H), 2848cm -1(C-H), 1712cm -1(C=O) urethane acid amides, 1524cm -1(C-N), 1438cm -1(C-N), 1356cm -1(C-O), 1400-1000cm -1(C-F).By being dissolved among the MeOH and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 2 being further purified.
Embodiment 3: the synthetic and sign oligomeric fluorochemical of the red sulphonyl of compound 3().
With compound 2(2.0g, 1.71mmol acid) be dissolved in the dry DMF (25mL).With the solution cooling, add DIC(0.215g, 1.71mmol) and at N 2Lower at room temperature with solution stirring 2 hours.To be in TEA(0.345g, 3.41mmol in the dry DMF (9mL)) and the Methionin (KD) (0.718g, 1.71mmol) of dansyl mark add in the compound 2 of activation, and at N 2At room temperature solution is continued to stir well 12 hours down.This product (compound 3) carries out purifying with positively charged ion and fluorine SPE, and reclaims by rotary evaporation.GPC(diox moving phase): do not detect free KD, and the polymkeric substance peak has strong UV absorbancy. 1HNMR (400MHz, CDCl 3) δ (ppm) 7.14-8.59 (aromatic series H, KD) 4.46-4.66 (CH 2-N, KD), 4.28-4.48 (CH 2-O, BAL), 3.90-4.17 (CH 2-O-CO, PTMO), 3.31-3.54 (CH 2-O, PTMO), 3.06-3.26 (C H 2-NH, LDI), 2.81-3.00 (CH 3, KD) 2.32-2.58 (CH 2-CF 2-, BAL), 1.08-1.94 (CH 2, PTMO, LDI and KD).The high performance liquid chromatography of compound 3 (HPLC) is analyzed: injection is in concentration range among the MeOH from the sample of 0.0005mg/mL to 50mg/mL and uses the buffer reagent moving phase of MeOH/pH 9 to analyze.At 21 minutes free KD(standardized solution of wash-out), and at 35 minutes wash-out compounds 3, and the evidence that not free KD pollutes.
Embodiment 4: the synthetic and sign oligomeric fluorochemical of compound 4(silicone).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at DMAc(80mL) in make hydroxy-end capped PDMS(10g, 13.8mmol) and LDI(5.848g, 28mmol) reacted 2 hours.Perfluoro alcohol (12.745g, 30mmol) is dissolved in DMAc(32mL) in, and add in this reaction, and at N 2Lower at room temperature the stirring spent the night.GPC(THF moving phase): retention time 25.5 minutes. 1H NMR(400MHz,CDCl 3)δ(ppm)4.26-4.48(-CH 2-O,BAL)，3.93-4.09(-CH 2-O-CO，PDMS)，3.74(CH 3，LDI)，3.08-3.26(C H 2-NH，LDI),2.33-2.60(-CH 2-CF 2-,BAL),1.61-1.76(-Si-O-CH 2,PDMS),1.13-1.93(CH 2,LDI),0.49-0.60(CH 2-C H 2-CH 2,PDMS),0.025-0.36(CH 3,PDMS)。Dsc analysis: T g=-40 ° of C.Ultimate analysis: 21.2%F.
Embodiment 5: the synthetic and sign oligomeric fluorochemical of compound 5(BPH).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(70mL) in make polyester glycol (BPH, 10.0g, 10mmol) and LDI(4.24g, 20mmol based on the neopentyl glycol Tetra hydro Phthalic anhydride) reacted 2 hours.Perfluoro alcohol (9.24g, 22mmol) is dissolved in anhydrous DMAc(25mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By solvent extraction and kation S PE product (compound 5) is carried out purifying.GPC(THF moving phase): retention time 25.4 minutes. 1H NMR (400MHz, CDCl 3) δ (ppm) 7.41-7.79 (aromatic series H, BPH), 4.25-4.44 (CH 2-O, BAL), 4.05-4.21 (CH 2-O, BPH), 3.67-3.79 (CH 3, LDI), 3.06-3.25 (CH 2-NH, LDI), 2.32-2.56 (CH 2-CF 2-, BAL), 1.26-1.90 (CH 2, LDI), 0.86-1.11 (CH 3, BPH).Surface analysis (XPS): 31.4%F.Ultimate analysis: 15.64%F.Dsc analysis: T g=25 ° of C.Contact angle (water advance (angle)): 106 °.Texture analysis: 1.8g.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 5 being further purified.
Embodiment 6: the synthetic and sign oligomeric fluorochemical of compound 6(PEG).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous THF(54mL) in make PEG(7.65g, 7.65mmol) and LDI(3.25g, 15.3mmol) reacted 2 hours.Perfluoro alcohol (7.07g, 16.8mmol) is dissolved in anhydrous THF(18mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By precipitation and kation S PE product (compound 6) is carried out purifying.GPC(THF moving phase): retention time 24 minutes. 1H NMR(300MHz,CDCl 3)δ(ppm)4.25-4.44(-CH 2-O,BAL),4.08-4.15(-CH 2-O-CO,PEG),3.70-3.75(-CH 3,LDI),3.55-3.77(-CH 2,PEG),3.10-3.30(CH 2-NH,LDI),2.32-2.60(-CH 2-CF 2-,BAL),1.20-1.90(CH 2,LDI)。Dsc analysis: T g=-45.5 ° of C, T m=21.7 ° of C.Contact angle is analyzed (water advance (angle)): 108.7 °.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 6 being further purified.
Embodiment 7: the synthetic and sign oligomeric fluorochemical of compound 7(NPG542).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous THF(133mL) in make neopentyl glycol (NPG, 3.0g, 28.8mmol) and LDI(7.63g, 36mmol) reacted 2 hours.Perfluoro alcohol (6.65g, 15.8mmol) is dissolved in anhydrous THF(83mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By precipitation and kation S PE product (compound 7) is carried out purifying.GPC(THF moving phase): retention time 26 minutes. 1H NMR(300MHz,CDCl 3)δ(ppm)4.23-4.48(-CH 2-O,BAL),3.85-4.10(-CH 2-O-CO,NPG),3.70-3.73(-CH 3,LDI),3.10-3.20(CH 2-NH,LDI),2.30-2.58(-CH 2-CF 2-,BAL),1.25-1.85(CH 2,LDI),0.80-1.05(CH 3,NPG)。Surface analysis (XPS): 18.75%F.Ultimate analysis: 14.46%F.Dsc analysis: T g=-3 ° of C, T m=161 ° of C.Contact angle is analyzed (water advance (angle)): 106.9 ° of C.Texture analysis: 1g.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 7 being further purified.
Embodiment 8: the synthetic and sign oligomeric fluorochemical of compound 8(PEGA).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(43.5mL) in make poly-(glycol adipate) (PEGA, 7.45g, 2.98mmol) and LDI(1.26g, 5.96mmol) reacted 2 hours.Perfluoro alcohol (2.75g, 6.55mmol) is dissolved in anhydrous DMAc(7mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By precipitation and kation S PE product (compound 8) is carried out purifying.GPC(THF moving phase): retention time 22.5 minutes. 1H NMR(300MHz,CDCl 3)δ(ppm)4.30-4.40(-CH 2-O,BAL),4.20-4.30(-CH 2-O-CO,PTMO;-NH-OCO-O-C H 2 -CH 2-，PEGA),3.75(CH 3,LDI),3.58-3.72(-O-C H 2 -C H 2 -O-，PEGA),3.12-3.24(C H 2-NH,LDI),2.30-2.70(-CH 2-CF 2-,BAL;-OCO-O-C H 2 -,PEGA),1.25-2.0(CH 2LDI;-CH 2C H 2 CH 2-,PEGA)。Surface analysis (XPS): 41.06%F.Ultimate analysis: 25.76%F.Contact angle is analyzed (water advance (angle)): 118.5 °.Dsc analysis: T g=-43 ° and 156 °.Viscosity Analysis (37 ° of C): 144Pa.s.Texture analysis: 66g.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 8 being further purified.
Embodiment 9: the synthetic and sign oligomeric fluorochemical of compound 9(HPCN TMX).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(150mL) in make hexa-methylene polycarbonate diol (hexamethylene polycarbonate diol) (HPCN, 25.0g, 12.5mmol) and LDI(6.10g, 25mmol) reacted 2 hours.Perfluoro alcohol (11.55g, 27.5mmol) is dissolved in anhydrous DMAc(29mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By solvent extraction and kation S PE product (compound 9) is carried out purifying.GPC(diox moving phase): retention time 22.6 minutes. 1H NMR (300MHz,CDCl 3)δ(ppm)7.2-7.45(-CH,TMX),4.30-4.43(-CH 2-O,BAL),4.04-4.20(-CH 2-C H 2 -O-CO,HPCN),3.90-4.03(-C H 2 -O-CO-NH,HPCN),2.25-2.55(-CH 2-CF 2-,BAL),1.13-1.80(CH 2,HPCN;CH 3,TMX)。Ultimate analysis: 10.5%F.Dsc analysis: T g=-32.2 ° of C, T m=147 ° of C.Surface analysis (XPS): 33.17%F.Viscosity Analysis (37 ° of C): 360Pa.s.Texture analysis: 170g.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 9 being further purified.
Embodiment 10: the synthetic and sign oligomeric fluorochemical of compound 10(EG).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous THF(60mL) in make ethylene glycol (EG, 1.5g, 24.2mmol) and LDI(10.3g, 48.4mmol) reacted 2 hours.Perfluoro alcohol (22.4g, 53.2mmol) is dissolved in anhydrous THF(56mL) in, and add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By precipitation and kation S PE product (compound 10) is carried out purifying.GPC(THF moving phase): retention time 27 minutes. 1H NMR(300MHz,CDCl 3)δ(ppm)4.23-4.48(-CH 2-O,BAL),4.10-4.25(-CH 2-O-CO,EG),3.75(-CH 3,LDI),3.10-3.28(CH 2-NH,LDI),2.36-2.60(-CH 2-CF 2-,BAL),1.25-1.85(CH 2,LDI)。Surface analysis (XPS): 36.87%F.Ultimate analysis: 27.51%F.Dsc analysis: T g=-3 ° of C.Contact angle is analyzed (water advance (angle)): 130.7 °.Viscosity Analysis (37 °): 2397Pa.s.Texture analysis: 29.1g.
Embodiment 11: the synthetic and sign oligomeric fluorochemical of compound 11(HPH).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous THF(122mL) in make based on 1 the polyester glycol of 6-hexylene glycol-Tetra hydro Phthalic anhydride (HPH, 20.0g, 10mmol) and LDI(4.24g, 20mmol) reacted 2 hours.Perfluoro alcohol (9.24g, 22mmol) is dissolved in anhydrous THF(23mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By precipitation and kation S PE product (compound 11) is carried out purifying.GPC(THF moving phase): retention time 23.8 minutes. 1H NMR (300MHz, CDCl 3) δ (ppm) 7.52-7.68 (CH, aromatic ring HPH), 4.30-4.40 (CH 2-O, BAL), 4.10-4.22 (C H 2 -O-CO, HPH), 4.0-4.08 (CH 2-COO-NH-, HPH), 3.70-3.75 (CH 3, LDI), 3.10-3.21 (CH 2-NH, LDI), 2.32-2.52 (CH 2-CF 2-, BAL), 1.24-1.85 (CH 2, LDI and HPH).Dsc analysis: T g=-13 ° of C.Contact angle is analyzed (water advance (angle)): 119.1 °.Surface analysis (XPS): 40.74%F.Ultimate analysis: 9.18%F.Viscosity Analysis (37 ° of C): 896Pa.s.Texture analysis: 113.9g.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 11 being further purified.
Embodiment 12: synthetic and sign compound 12(P3611 oligopolymer).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at DMAc(17mL) in make poly-alkoxylation polyvalent alcohol (P3611) (1g, 3.8mmol) and LDI(2.391g, 11.28mmol) reacted 2 hours.Perfluoro alcohol (5.211g, 12.4mmol) is dissolved in DMAc(13mL) in, add in this reaction, and at N 2Stir under the lower room temperature and spend the night.GPC(THF moving phase): retention time 23 minutes. 1H NMR (300MHz, CDCl 3) δ (ppm) 4.25-4.51 (CH 2-O, BAL), 3.93-4.07 (CH 2-O-CO, P3611), 3.73 (CH 3, LDI), 3.05-3.25 (C H 2 -NH, LDI), 2.31-2.57 (CH 2-CF 2-, BAL), 1.21-1.93 (CH 3-CH 2-, P3611, and CH 2, LDI), 0.79-0.95 (CH 3, P3611).Ultimate analysis: 33%F.
Embodiment 13: the synthetic and sign oligomeric fluorochemical of compound 13(hexafluoro pentanediol).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(20mL) in make 2,2,3,3,4,4-hexafluoro-1,5-PD (HPD, 1.04g, 4.9mmol) and LDI(2.07g, 9.75mmol) reacted 2 hours.With methyl alcohol
Figure BDA00002022515600501
Add in this reaction, and at N 2Lower at room temperature the stirring spent the night.With removal of solvents, and by kation S PE product (compound 12) is carried out purifying.Gpc analysis: product is dissolved in the diox, and moves in the GPC system with polystyrene columns and UV detector. 1H NMR(400MHz,CDCl 3)δ(ppm)4.53-4.75(-C H 2 -CF 2，HPD)，4.30-4.40(-CH，LDI)，3.70(-CH 3，LDI)，3.60-3.65(CH 3-O,MeOH),3.10-3.25(CH 2-NH,LDI),1.25-1.85(CH 2,LDI)。Compound 12 is mixed in the Carbothane 85A alkaline polymer with 5wt% additive form, makes 0.1g/mL solution with the DMAc solvent.In the teflon mould, cast the film of mixture, and under 50 ° of C dry 24 hours, and then under 50 ° of C under vacuum dry 24 hours.The surface analysis of film mixture (XPS): 1.78%F.
Embodiment 14: the synthetic and sign oligomeric fluorochemical of compound 14(perfluor dodecanediol (Perfluoro dodecanediol oligofluoro)).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(20mL) in make 1H, 1H, 12H, 12H-perfluor-1,12-dodecanediol (PDD, 1.02g, 1.81mmol) and LDI(0.77g, 3.63mmol) reacted 2 hours.With methyl alcohol Add in this reaction, and at N 2Lower at room temperature the stirring spent the night.With removal of solvents, and by kation S PE product (compound 14) is carried out purifying.Gpc analysis: product is dissolved in the diox, and moves in the GPC system with polystyrene columns and UV detector. 1H NMR(400MHz,CDCl 3)δ(ppm)4.53-4.75(-CH 2-CF 2,PDD),4.30-4.40(-CH,LDI),3.70(-CH 3,LDI),3.60-3.65(CH 3-O,MeOH),3.10-3.25(CH 2-NH,LDI),1.25-1.85(CH 2,LDI)。Compound 14 is mixed in the Carbothane 85A alkaline polymer with 5wt% additive form, makes 0.1g/mL solution with the DMAc solvent.In the teflon mould, cast the film of mixture, and under 50 ° of C dry 24 hours, and then under 50 ° of C under vacuum dry 24 hours.The surface analysis of film mixture (XPS): 35.63%F.
Embodiment 15: synthetic and sign compound 15(dihydroxyphenyl HFC-236fa).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(20mL) in make 2,2-two (4-hydroxyphenyl) HFC-236fa (BHP, 1.08g, 3.21mmol) and LDI(1.37,6.44mmol) reacted 4 hours.With methyl alcohol
Figure BDA00002022515600512
Add in this reaction, and at N 2Lower at room temperature the stirring spent the night.Come separated product (compound 15) by removing solvent.Gpc analysis: product is dissolved in the diox, and moves in the GPC system with polystyrene columns and UV detector. 1H NMR(400MHz,DMSO)δ(ppm)6.98-7.03(-CH-CCF 3,BHP),6.75-6.83(-CH-CO,BHP),4.53-4.75(NH,LDI),4.30-4.40(-CH,LDI),3.65(-CH 3,LDI),3.45-3.51(CH 3-O,MeOH),3.10-3.25(CH 2-NH,LDI),1.25-1.85(CH 2,LDI)。Compound 15 is mixed in the Carbothane 85A alkaline polymer with 5wt% additive form, makes 0.1g/mL solution with the DMAc solvent.In the teflon mould, cast the film of mixture, and under 50 ° of C dry 24 hours, and then under 50 ° of C under vacuum dry 24 hours.The surface analysis of film mixture (XPS): 3.82%F.
Embodiment 16: the synthetic and sign oligomeric fluorochemical of compound 16(HEMA combination).
With compound 2(10.0 gram, approximately 8mmol acid), the DMAP(0.488 gram, 4mmol), the HEMA(6.247 gram, 48mmol) and DCM(50mL) add in the 250mL flask, and stir until all compound dissolutions.With the EDC(4.600 gram, 24mmol) add in this DCM solution, in case and the EDC dissolving, at N 2Lower at room temperature with solution stirring 24 hours, and lucifuge.By rotary evaporation (25 ° of C) reaction mixture is reduced into viscous liquid and water (3 * 400mL) washings three times.The product of washing is dissolved in (100mL, 100ppmBHT) in the diethyl ether, and by making this solution and MgSO 4Mix 1 hour with moisture removal.In the 250mL flask, make the solution clarification by gravity filtration, and pass through rotary evaporation (25 ° of C) with removal of solvents.Product (compound 16) be dissolved among the DMF again and use fluorine SPE(F-SPE) come purifying and reclaim by rotary evaporation. 1H NMR (300MHz, CDCl 3) δ (ppm) 6.09-6.15 (HEMA vinyl H), 5.58-5.63 (vinyl H, HEMA), 4.83-5.78 (CH 2), 4.27-4.49 (CH 2-O, BAL; CH 2, HEMA), 4.01-4.15 (CH 2-OCO-, PTMO), 3.75 (little CH 3Signal), 3.31-3.50 (CH 2-O-, PTMO), 3.07-3.23 (C H 2 -NH, PTMO), 2.36-2.56 (CH 2-CF 2-, BAL), 1.91-1.96 (CH 3, HEMA) 1.27-1.74 (CH 2, PTMO and LDI).Gpc analysis (diox moving phase): retention time 26.5 minutes.In analyzing, this does not detect free HEMA monomer.IR analyzes: 1634cm -1(C=C).
Embodiment 17: the synthetic and sign oligomeric fluorochemical of compound 17(FEO1).
With PTMO(10g, 0.0097mol, degassed) be dissolved in anhydrous DMAc(50mL) in.Lysinediisocyanate (4.11g, 0.020mol, distillation) and DBDL catalyzer are dissolved in anhydrous DMAc(25mL) in and be added dropwise in this PTMO solution.Under nitrogen atmosphere, prepolymer reaction remained under the 60-70 ° of C and continue 2 hours.With perfluorinated acrylate (4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11-, 17 fluoro-2-hydroxyl undecyl acrylate) (FEO1,12.058g, 0.022mol) is dissolved in DMAc(25mL with DBDL) in and be added dropwise in this pre-polymer solution, at N 2Lower at room temperature the stirring spent the night.Product is deposited in the water (2L), is dissolved in again (100mL, 100ppm BHT) in the diethyl ether, use MgSO 4Drying and filtration.Ethereal solution is splashed in the hexane (400mL) be used for precipitated product and extract unreacted reagent.Repeat twice with the hexane decant and with solvent extraction.The product (compound 17) of purifying is dissolved in (50mL) in the diethyl ether, and at room temperature by rotary evaporation with removal of solvents. 1H NMR (400MHz, CDCl 3) δ (ppm) 6.40-6.52 (vinyl H, FEO1), 6.09-6.23 (vinyl H, FEO1), 5.80-5.95 (vinyl H, FEO1), 4.15-4.53 (C-H, FEO1; O-CH 2-FEO1), 4.00-4.15 (CH 2-O-CO, PTMO), 3.75 (CH 3, LDI), 3.31-3.50 (CH 2-O, PTMO), 3.05-3.25 (C H 2-NH, LDI), 2.35-2.61 (CH 2-CF 2-, FEO1), 1.25-1.73 (CH 2, PTMO and LDI).Gpc analysis (diox moving phase): retention time 26 minutes.In analyzing, this does not detect free FEO1 monomer.IR analyzes: 1634cm -1(C=C).
Embodiment 18: the synthetic and sign oligomeric fluorochemical of compound 18(FEO3).
With PTMO(10g, 0.0097mol, degassed) be dissolved in anhydrous DMAc(50mL) in.Lysinediisocyanate (4.241g, 0.02mol, distillation) and dibutyltin dilaurate catalyst are dissolved in anhydrous DMAc(22mL) in and be added drop-wise in this PTMO solution.At N 2The lower prepolymer reaction is remained under the 60-70 ° of C continues 2 hours.Perfluorinated acrylate (3-(perfluor-3-methyl butyl)-2-HPMA) (FEO3,9.068g, 0.022mol) is dissolved in DMAc(23mL with dibutyl tin laurate) in and be added drop-wise in the pre-polymer solution.At N 2Reactor is stirred to spend the night.Product is deposited in (2L) in the water, is dissolved in again (100mL, 100ppm BHT) in the diethyl ether, use MgSO 4Drying, and filter.This ethereal solution is splashed in the hexane (400mL) be used for precipitated product and extract unreacted reagent.Repeat twice with the hexane decant and with this solvent extraction.The product (compound 18) of purifying is dissolved in (50mL) in the diethyl ether, and at room temperature in flow hood (flow hood), passes through evaporation with removal of solvents. 1H NMR (400MHz, CDCl 3) δ (ppm) 6.10-6.16 (vinyl H, FEO3), 5.66-5.89 (vinyl H, FEO3), 4.27-4.41 (O-CH 2-, FEO3), 4.15-4.27 (O-CH 2-, FEO3) 4.00-4.14 (CH 2-O-CO, PTMO), 3.75 (CH 3, LDI), 3.27-3.52 (CH 2-O, PTMO), 3.05-3.21 (C H 2-NH, LDI), 2.34-2.61 (CH 2-CF 2-, FEO3), 1.90-1.99 (CH 3, FEO3), 1.22-1.90 (CH 2, LDI and PTMO).Gpc analysis (diox moving phase): retention time 26.5 minutes.In analyzing, this does not detect free FEO3 monomer.IR analyzes: 1634cm -1(C=C).
Embodiment 19: the synthetic and sign oligomeric fluorochemical of compound 19(Tris).
The EDC association reaction of method A:Tris
With compound 2(10g, 4.4mmol), EDC and the molar ratio of DMAP(take acid groups: EDC:DMAP as 1:6:0.5) be dissolved in the dry DMF (200mL).With Tris(take Tris: acid groups is as the molar ratio of 1.1:1) add in this reaction mixture.At room temperature at N 2Under make this solution reaction 24 hours.Under 40 ° of C with the DMF solvent evaporation.At room temperature use diethyl ether (3 * 100mL) extraction viscous residues.EDC and Tris are insoluble in the cold ether.Ethereal solution evaporation with clarification.Under 40C under vacuum with white sticky product (compound 19-a) dried overnight.Ultimate analysis: 25.57%F.IR analyzes: 3330cm -1(O-H), 1110cm -1(C-OH), 1160cm -1(C-F), 1220cm -1(C-O-C). 1H NMR(300MHz,CDCl 3)δ(ppm)2.38(C TrisCH 2OH),1.73(C Tris-NH)。Determining of OH quantity: react by in pyridine, making compound 19-a and excessive acetic acid acid anhydride, and then carrying out back titration (use phenolphthalein as indicator) with potassium hydroxide base determines the hydroxy radical content of compound 19-a (it is for dangle (side joint, pendent) Tris is unique).The result: OH quantity is 2.4113mmol/g.
The K of method B:Tris 2CO 3Association reaction
With compound 1(3.05g, approximately 2.6mmol) be dissolved in the anhydrous methanol (100mL).Add the mixture of trishydroxymethyl ethylamine (Tris, 0.63g, 5.2mmol) and Anhydrous potassium carbonate (0.72g, 5.2mmol).Under 45 ° of C with this reaction mixture refluxed seven days.With this reaction mixture cooling, and utilize cationic exchange and fluorine solid state reaction that this solution is carried out purifying.Under vacuum with dry 48 hours (the 50 ° of C) of final product (compound 19-b). 1H NMR (300MHz, CDCl 3) δ (ppm) 4.25-4.50 (CH 2-O, BAL), 3.95-4.20 (CH 2-OCO-, PTMO), the 3.75 (CH of reduction 3Signal, LDI), 3.57-3.83 (CH 2, Tris), 3.30-3.56 (CH 2O, PTMO), 3.04-3.28 (C H 2 NH-, PTMO), 2.29-2.59 (CH 2CF 2-, BAL), 1.17-1.97 (CH 2-, PTMO and LDI).HPLC analyzes (reversed-phase HPLC, C18 post, methyl alcohol and pH 9PBS moving phase (gradient)): elution time 34.6 minutes.Compound 19-b is mixed in the Carbothane 85A alkaline polymer with 5wt% additive form, makes 0.1g/mL solution with DMAc solution.In the teflon mould, cast the film of mixing, and under 50 ° of C, solidified 24 hours, and then under 50 ° of C under vacuum dry 24 hours.Use 90 ° of take-off angles by XPS the air contacting surface of film to be analyzed.Ultimate analysis: Carbothane 0%F; Carbothane+5wt% compound 19-b 36.3%F.Contact angle is analyzed: use solvent casting technology (solvent casting techniques) that compound 19-b is mixed in Carbothane 85A and ethylene-co-vinyl acetate (EVA) alkaline polymer with the 5wt% form of mixtures.Make water EVA carry out the contact angle analysis.105 °+/-2 ° (hydrophobicity), 19-b:15 ° of EVA+ compound+/-2 ° (wetting ability).Carbothane 85A:102 °+/-4 ° (hydrophobicity), 19-b:18 ° of Carbothane+ compound+/-5 ° (wetting ability).
Embodiment 20: the synthetic and sign oligomeric fluorochemical of compound 20(Tris-Br).
At N 2Lower with the oligomeric fluorochemical of compound 19(Tris) (10g, 4.0mmol) (dry in front) and the molar ratio of TEA(take the TEA:OH group as 1.2:1) be dissolved in anhydrous CH 2Cl 2(50mL).In ice-water bath, solution is cooled off.Under nitrogen atmosphere with the 10%BIBB/CH of stoichiometric 2Cl 2Solution is added drop-wise to compound 19/CH 2Cl 2In the solution.At room temperature this mixture was stirred 24 hours, then filter with removing TEA-HBr salt.Water (10mL) is with filtrate washing three times.At room temperature with CH 2Cl 2Evaporation.Obtain a kind of filbert viscous solid product (compound 20).Ultimate analysis: 17.42%F, 13.65%Br. 1H NMR(300MHz,CDCl 3)δ(ppm)2.05(C(C H 3 ) 2Br)。
Embodiment 21: the synthetic and sign oligomeric fluorochemical of compound 21(Tris-PHEMA-Br).
With the oligomeric fluorochemical of compound 20(Tris-Br) (2.5g, 1mmol) be dissolved in DMF(10mL) in.With CuBr(0.143g, 1mmol) and HMTETA(0.253g, 1.1mmol) add in this solution.This flask is connected on the vacuum pipeline and by liquid nitrogen freezing-thawing three times.Fill this flask with ultra-high purity nitrogen, and add HEMA(2.86g, the 22mmol of new distillation).In oil bath, this flask is heated to 50 ° of C and continues 20 hours.By in frozen water, this flask being cooled off to stop this polyreaction.Under 40 ° of C, from solution, evaporate DMF.Viscous solid is dissolved among the THF, and filters by silicagel column, with removing catalyzer.At room temperature from filtrate the evaporation THF after, under 40 ° of C under vacuum with this solid product (compound 21) dried overnight.Ultimate analysis: 10.21%F; 0.28%Br. 1H NMR(300MHz,DMSO)δ(ppm)4.80(CH 2O H,HEMA),3.92(COOC H 2 ,HEMA),3.60(C H 2 OH,HEMA),1.79(C H 2 CCH 3,HEMA),0.80(CH 2CC H 3,HEMA)。Should be recorded as 9.01 * 10 by average (polystyrene equivalent) molecular weight 4G/mol, wherein polymolecularity is 1.65.The weight average MW of this final product is significantly greater than compound 20.These data show the successful polyreaction of final product.Based on the OH volumetry, can partly come to determine mean polymerisation degree for the PHEMA of this molecule.Theoretical OH value is 6.366mmol/g, and titration value is 6.386mmol/g.Based on OH quantity, quantitatively in conjunction with this HEMA, and be 21.7 for the mean polymerisation degree of PHEMA branch.
Embodiment 22: the synthetic and sign oligomeric fluorochemical of compound 22(Tris-PMAA-Br).
With Tert-butyl Methacrylate (tBMA, 2.10g, 15mmol), CuBr(0.149g, 1mmol) and dimethylbenzene (4mL) add in the flask.This flask seals with diaphragm of rubber (rubber septum), and cools off in frozen water.Make the ultra-high purity nitrogen purging continue 15 minutes by this mixture.Then add HMTETA(by syringe and use in front the nitrogen purging mistake; 0.46g, 2.0mmol).Become clarification and after color becomes bright green, add the compound 20(0.5858g be in the acetone (5mL), the Br group of 1mmol at solution) solution.In oil bath this flask being heated to 70 ° of C spends the night.By in frozen water, this flask being cooled off to stop polyreaction.This solution THF(20mL) dilutes, and filter for removing catalyzer by silicagel column.Filtrate is deposited in the water, and under 30 ° of C under vacuum with the solid polymer dried overnight.Solid polymer (1g) is dissolved in CHCl 3(9mL) and CF 3COOH(1mL) in the solution.At room temperature with this solution stirring 20 hours.This polymkeric substance becomes gel sample semisolid in solution.By filtering removal of solvents, and use CHCl 3With twice of solids wash and filter.At room temperature under vacuum, all liquid resistates is removed.Under 40 ° of C under vacuum with solid product (compound 22) dried overnight.The COOH quantity of titration is 8.8592mmol/g.Based on titration results and stoichiometry, determine that the tBMA transformation efficiency is 96.7%, and the mean polymerisation degree of the PMAA branch of calculating is 14.6.
Embodiment 23: the synthetic and sign oligomeric fluorochemical of compound 23(Tris-PVP-Br).
With l-vinyl-2-pyrrolidone (VP, 3.33g, 30mmol), compound 20(1mmol) and CuBr(0.143g, 1mmol) add in the flask.This flask seals with diaphragm of rubber and cools off in frozen water.Use N 2This mixture is purged 30 minutes.With 2, (2,2 '-Dipyridyl) (BPY uses N to 2 '-dipyridyl in front 2Purged 0.156g, 1mmol) add in this mixture.In oil bath, this flask is heated to 100 ° of C and continues 20 hours.By in frozen water, this flask being cooled off to stop polyreaction.This solution CH 2Cl 2(200mL) dilute, and filter by alumina column, with removing catalyzer.At room temperature from filtrate, evaporate CH 2Cl 2Afterwards, under 40 ° of C under vacuum with this solid product dried overnight.Ultimate analysis: 0.67%F; 1.10%Br.Based on F and Br content, the VP transformation efficiency reaches 78.6%, and being transformed into (translating) is 60 for the mean polymerisation degree of PVP branch. 1H NMR (300MHz, CDCl 3) δ (ppm) 7.00 (CH 2C H, PVP), 4.92 (C H 2CH, PVP), 3.48 (NC H 2 , PVP), 3.40 (C H 2OC H 2, urethane), 2.47 (COCH 2, PVP), 2.10 (CH 2C H 2 CH 2,PVP), 1.62 (CH 2C H 2 C H 2 CH 2, urethane).
Embodiment 24: the synthetic and sign oligomeric fluorochemical of compound 24(Accmer).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(50mL) in make Accmer(7.0g, 7.0mmol) and LDI(2.97g, 14mmol) reacted 2 hours.Perfluoro alcohol (6.45g, 15.4mmol) is dissolved in anhydrous DMAc(16.2mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.By kation S PE this product (compound 24) is carried out purifying.GPC(THF moving phase): retention time 25.5 minutes. 1H NMR (300MHz, CDCl 3) δ (ppm) 4.24-4.46 (CH 2-O, BAL), 3.94-4.13 (CH 2-O-CO, Accmer), 3.75 (CH 3, LDI), 3.38-3.64 (CH 2-O, Accmer), 3.16 (C H 2-NH, LDI), 2.29-2.60 (CH 2-CF 2-, BAL), 1.16-1.96 (CH 2, Accmer and LDI), 0.84 (CH 2, Accmer).Dsc analysis: T g=-47 ° of C, T m=23 ° of C.Ultimate analysis: 17%F.By being dissolved in the acetone and with 1000MWCO RCF regenerated cellulose film dialysis three days compound 24 being further purified.Ultimate analysis: 13.3%F.Compound 24 drippage curtain coatings (dripping casting, drop cast) are used for surface analysis (XPS) to the nylon: 45%C, 29%F, 5%N, 21%O.
Embodiment 25: the synthetic and sign oligomeric fluorochemical of compound 25(Accmer TMX).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(25mL) in make Accmer(3.0g, 3.0mmol) and TMX(1.466g, 6.0mmol) reacted 2 hours.Perfluoro alcohol (2.778g, 6.0mmol) is dissolved in anhydrous DMAc(25mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.This product has 27 minutes GPC(THF moving phase) retention time.By kation S PE product is carried out purifying. 1HNMR analyzes consistent with the chemical structure of prediction. 1H-NMR (300MHz, CDCl 3) δ (ppm) 7.1-7.6 (aromatic series-CH 2, TMX), 4.3-4.4 (CH 2-O, BAL;-NH-carbamate), 3.9-4.0 (CH 2-O-CO, Accmer), 3.4-3.8 (CH 2-O-, Accmer), 3.38 (CH 2-, Accmer), 2.3-2.5 (CH 2-CF 2-, BAL), 1.5-2.0 (CH 3, TMX), 1.2 (CH 3, Accmer), 0.9 (CH 3, Accmer).Ultimate analysis: 17%F.Compound 25 drippage curtain coatings are used for surface analysis (XPS) to the nylon: 54%C, 27%F, 3%N, 15%O.
Compound 26: the synthetic and sign oligomeric fluorochemical of compound 26(Accmer HDI).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(25mL) in make Accmer(3.0g, 3.0mmol) and HDI(1.009g, 6.0mmol) reacted 2 hours.Perfluoro alcohol (2.778g, 6.0mmol) is dissolved in anhydrous DMAc(25mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.This product has 25 minutes GPC(THF moving phase) retention time.By kation S PE product is carried out purifying. 1HNMR analyzes consistent with the chemical structure of expection. 1H-NMR (300MHz, CDCl 3) δ (ppm) 4.3-4.4 (CH 2-O, BAL;-NH-carbamate), 3.9-4.0 (CH 2-O-CO, Accmer), 3.5-3.7 (CH 2-O-, Accmer; N H-COO-, the HDI-Accmer carbamate), 3.38 (CH 2-, Accmer), 3.1-3.25 (NH- CH 2 -, HDI), 2.3-2.5 (CH 2-CF 2-, BAL), 1.3-1.6 (CH 2-, HDI), 0.9 (CH 3, Accmer).Compound 26 drippage curtain coatings are used for surface analysis (XPS) to the nylon: 44%C, 46%F, 3%N, 7%O.
Embodiment 27: the synthetic and sign oligomeric fluorochemical of compound 27(Accmer THDI).
At N 2Lower, under 70 ° of C in the presence of the DBDL catalyzer, at anhydrous DMAc(25mL) in make Accmer(3.0g, 3.0mmol) and THDI(1.045g, 6.0mmol) reacted 2 hours.Perfluoro alcohol (2.778g, 6.0mmol) is dissolved in anhydrous DMAc(25mL) in, add in this reaction, and at N 2Lower at room temperature the stirring spent the night.This product has 25 minutes GPC(THF moving phase) retention time.By kation S PE this product is carried out purifying. 1HNMR analyzes consistent with the chemical structure of expection. 1H-NMR (300MHz, CDCl 3) δ (ppm) 4.3-4.4 (CH 2-O, BAL;-NH-carbamate), 3.9-4.0 (CH 2-O-CO, Accmer), 3.4-3.8 (CH 2-O-, Accmer), 3.38 (CH 2-, Accmer), 2.3-2.5 (CH 2-CF 2-, BAL), 1.2 (CH 3, Accmer), 0.9 (CH 3, Accmer).Ultimate analysis: 12%F.Compound 27 drippage curtain coatings are used for surface analysis (XPS) at nylon: 55%C, 25%F, 3%N, 17%O.
Embodiment 28: the compound of selection and the sterilization of balloon catheter.
The compound that to select from embodiment 1-27 is weighed in the polypropylene tapered tube of adding a cover with the thin paper (lint-free tissue) that does not contain velveteen, places the sterilization pouch, and sterilizes by EtO.By GPC the compound of sterilization is analyzed, and these results are compared with the front graphic representation of sterilization.For not observing change with sample afterwards before the sterilization.
Prepare compound 24 and PTX mixture according to the experimental program of setting up, be weighed in the polypropylene tapered tube of adding a cover with the thin paper (lint-free tissue) that does not contain velveteen, place the sterilization pouch, and sterilize by EtO.The mixture of sterilization is analyzed and compared with their sterilizations graphic representation before by GPC and HPLC.After compound 24 and PTX sterilization, do not observe change among both.
Also with EtO the balloon catheter that is coated with compound 1, compound 24 and compound 24+PTX is sterilized.By GPC to sterilization and unpasteurized balloon catheter analyze, and compare with afterwards molecular weight graphic representation before will sterilize.MW before the sterilization: compound 1:8655, compound 24:4212, compound 24+PTX:4212.MW after the sterilization: compound 1:8960, compound 24:4841, compound 24+PTX:4849.PTX HPLC retention time (min): before the sterilization: 12.202, after the sterilization: 12.192.
Embodiment 29: the in vivo assessment of bio distribution and clearance rate in the model.
With compound 3(15mg) be dissolved in DMSO(25 μ L, 0.6g/mL) in and be expelled in the male Sprague-Dawley rat body.During 24 hours, take termly whole blood sample.(excite: 320nm and emission: 540nm) 3 fluorescent signals of compound in the whole blood sample are measured by the microwell plate analysis.Also for the fluorescent signal of compound 3 urine sample is analyzed.K e=0.044hr -1, T 1/2 (e), T 1/2 (summation)=15.7hr.
Embodiment 30: the coating coverage on visual (range estimation) balloon catheter.
With receive, launch a little and (unwrapped) PTCA balloon catheter of untiing is being in 90:10 toluene: dip-coating and spraying and dried overnight in 50 ° of C flow baking oven in the solution of the compound 3 among the THF.Use glass syringe and 18G tubing (tubing) that balloon catheter is launched a little.With having the air bag that applies spraying for the EFD fog system of the setting of compound 3.With shortwave UV lamp coating is assessed.The balloon catheter of untiing has maximum continuous coated, and then is the air bag that expands a little and twine.
Embodiment 31: be coated in compound 1 on the balloon catheter and in air, launch before and afterwards coating is assessed.
With compound 1(1.0g) be dissolved among the THF, and keep at room temperature until use.Use have for the EFD fog system of the setting of compound 1 with solution spray to the PTCA balloon catheter that launches a little, and in 50 ° of C flow baking oven dried overnight.Sem analysis show in air launch before and (have) afterwards thin, a flat coating.
Embodiment 32: the preparation of compound 1+PTX, and the PTX of the balloon catheter that applies loads.
With compound 1(0.4g) and PTX(0.04g-1.6g) be dissolved among the THF, and use immediately.(3.0mm * 17mm) also sprays or dip-coating to balloon catheter.Apply the air bag of spraying with the EFD fog system with the setting of developing for compound 1.For dip-coating, with Small clamp the fastening Aerial Work LT (scissor lift table) of using simultaneously in place of balloon catheter is elevated to certain height with dip-coating solution.In suitable solvent, the air bag itemize that applies is spent the night.Measure PTX heap(ed) capacity as interior mark with RP-HPLC with phenyl cyanide (benzonitrile).By changing dipping or spraying (ug/mm 2): the quantity of 0.2-6.0 is come the controlled loading amount.
Embodiment 33: inflammatory cell is to the assessment of compound 1,2,5-11,16-18,24 reactions.
Compound 1,2,5-11,24 are dissolved in THF or the toluene, and inject 96 hole polypropylene boards.At room temperature with solvent evaporation 24 hours, then place the mobile baking oven of 60 ° of C to continue 24 hours, at last dried overnight under vacuum.Compound 16-18 is dissolved in the toluene that comprises BPO initiator (quality of 1wt% compound 16-18).Toluene solution is injected 96 hole polypropylene boards, and at room temperature place semi-enclosed cell to continue 1 day.Then at N 2In 60 ° of C baking ovens that purge with compound 16-18 film hardening 12 hours, and vacuum-drying.For purpose relatively, the film of SIBS and 316 stainless steel insets (insert) is added in these orifice plates.With these orifice plate sterilizations 1 hour, after this each sample well came hydration with PBS under the UV lamp.In the presence of PMA with U937 monocytoid cell (2.5 * 10 5Individual cell) is inoculated in each hole, and these orifice plates hatched three days in moist incubator at 37 ° of C.Non-adherent cell (non-adhesive cell, non-adherent cells) is removed, and used the CyQuant assay method that adherent (adhesion) U937 scavenger cell is counted.
The film of embodiment 34:HCAEC migration by applying with the compound of selecting and 10wt%PTX.
With compound 1(0.1g) be dissolved in MeOH(0.5,1,2 and 4mL) in, and be pipetted into these solution (0.05mL) on the BD 8 μ m PET film insets and wicking by this inset.Also make compound 1 mix to form 1wt% and 10wt% solution with PTX, and these solution are coated on the film.In contrast, the SIBS polymers soln with proper concn is coated on the film.By SEM the coated film that obtains is checked, and confirm porosity by water by these films.In addition, come coating compound 3 with same procedure, fluorescence (Ex 320, Em 540nm) is measured to confirm the existence of coating: (uncoated film)=3.5, (compound 1)=0.6, (compound 3)=28.2.Use is cultured to the third generation by substratum and the fill-in of Lonza supply with HCAEC, and hunger is spent the night in serum free medium.Cell is extracted out and is suspended in the 0.5%FBS substratum again, and inoculation HCAEC(80000/ film inset).Following hole is filled with the 20%FBS substratum.Negative control is made of the uncoated film that has the 0.5%FBS substratum in the hole below.Positive control is made of the uncoated film that has the 20%FBS substratum in the hole below.After hatching 4 hours, these holes are enhanced, inner membrance is wiped cell, and lower facial mask surface is fixing and dye with DiffQuik.Gather the image of these films by microscopy, and record cell morphological characteristic and colony.
Use the clone from other kinds to repeat for the described migration assay of HCAEC for all compounds described in embodiment 1,5, the 7-11.
Embodiment 35: thrombocyte and Fibrinogen and compound 1,16 and 17 the interactional assessment of film.
Be dissolved in compound 1 in the toluene and at room temperature stirred 24 hours.Use have for the EFD fog system of the setting of compound 1 with this solution spray to 4cm * 4cm 316L stainless steel coupon (stopple coupon, coupon) on.In 50 ° of C flow baking oven with dry 20-24 hour of these coupons.Compound 16 and 17 is dissolved in the toluene that comprises BPO initiator (1wt% compound 16 and 17 quality), and this solution is injected 4cm * 4cm PTFE hole (6mL/ hole), and at room temperature PTFE is poured into a mould orifice plate and place semi-enclosed cell to continue 1 day.Then at N 2In 60 ° of C baking ovens that purge with compound 16 and 17 film hardenings 12 hours.In the volunteer's body that does not use medicine of health, obtain people's whole blood and collect have acid citrate glucose antithrombotics (6 parts of ACD are with respect to 1 part of blood) also or the centrifuge tube of low molecular weight heparin to final concentration 0.2U/mL.The thrombocyte that carries the collection blood of ACD separates and carries out mark with 0.5mCi/mL Na51Cr by centrifugal.Separate red hemocyte and washing from this ACD whole blood also.Thereby with the thrombocyte of Na51Cr mark with provide final PC and 40% hematocrit of 250,000 thrombocytes/μ L through the red corpuscle of washing and platelet poor plasma merging.At last, the 125I-Fibrinogen is added in the whole blood suspension so that it represents about 2% Fibrinogen total amount.In producing cone-plate equipment laminar flow and uniform shearing rate, by mobile whole blood platelet adhesion reaction is measured.The hole (wherein comprising the hematoblastic whole blood suspension of Na51Cr with 1.2mL) that the coupon (stopple coupon) that applies and film are placed this cone-plate equipment and measure lasting 15 minutes.Then wash these coupons (stopple coupon) and film with fresh buffer reagent, and radioactivity is measured and be associated based on the radioactivity of the initial whole blood suspension quantity with the Fibrinogen (125I-Fibrinogen) that adheres to thrombocyte (Na51Cr thrombocyte) and absorption with gamma counter.Compare with uncoated stainless steel coupon (stopple coupon), compound 1,16 and 17 has reduced platelet adhesion reaction and Fibrinogen absorption significantly.
Embodiment 36: the film with compound 1 comes evaluating protein to adhere to
The film of the compound 1 that uses among the embodiment 35 also is treated for evaluating protein and adheres to.These surfaces are oozed the tris buffer reagent and wash with waiting, and then are exposed to 2% sodium lauryl sulphate and continue 24 hours for eluted protein.Then carry out the SDS-PAGE gel.Protein band is sightless, shows that the albumen of minimum adheres to.
Embodiment 37:MEM wash-out assay method-compound 1,2,5-11,17 and 18 cytotoxicity assessment.
With compound 1,2 and 5-11 weighs and hatched in the MEM substratum 24 hours with the 4g:20mL ratio under 37 ° of C.Process in the same manner the film of compound 17 and 18.The inoculation L-929 l cell and under 37 ° of C at 5%CO 2In hatch to approach the cell monolayer that converges (sub-confluent).Replace growth medium in the triplicate culture with MEM extract (2mL).These triplicate cultures also are prepared into the positive and negative control.After 24 hours, at microscopically cell culture inspection is assessed cell characteristic and cytolysis per-cent.Under the condition of this test, these MEM extracts do not show and cause cytolysis or Cytotoxic evidence.
Embodiment 38: the direct contact measurement of compound 1.
With during test substances directly contacts, the epithelial vigor of HeLa is used to assess the potential cytotoxicity of compound 1.The sample of compound 1 by solvent cast (solvent cast) on the Supor strainer that agar is supported.Subsequently, in the presence of the MEM substratum, individual layer HeLa cell is directly cultivated on this strainer.After hatching 24 hours, dye with this Supor strainer flushing and with succinodehydrogenase.Dye to differentiate viable cell and the strainer by dyeing for the inspection of the cells exclude district (cell exclusion zones) around this mould material by positive purple, or low cell density is determined cytotoxicity.Each cytotoxic assay comprises a positive and negative control.
Embodiment 39: compound 24 and 18 dose-dependently cytotoxicity.
Compound 24 and 18 is dissolved among the DMSO and with different concns adds in the MEM substratum.The inoculation L-929 l cell and under 37 ° of C at 5%CO 2In hatch to obtain to approach the cell monolayer that converges.Replace growth medium in the triplicate culture with the MEM substratum of inclusion compound 24 and 18.These triplicate cultures also are prepared into the positive and negative control.After 24 hours hatch, cell viability checked under 1mg/ml by the WST-1 assay method and to report with respect to contrast % vigor form.Compound 24=99.8% and compound 18=96%.
Embodiment 40: compound 1,5,8,9,11 and 24 from the consistency of different therapeutical agents.
Compound 1,5,8,9 is mixed with troglitazone, C6-ceramide, Cerivastatin, prostaglandin E1, VEGF, taxol (taxol), rapamycin and dexamethasone mutually with 11.Compound 24 is mixed mutually with taxol, C6-ceramide, rapamycin and Ibuprofen BP/EP.Solution is dripped curtain coating on stainless steel coupon (stopple coupon) or nylon film, and be used for being separated and crystallization with microcosmic ground visual inspection on a macro scale.Compound 1,5,8,9,11 and 24 can be compatible with multiple therapeutical agent.
Embodiment 41:PTX transfers on the cardiac muscle from the nylon film that applies.
To be dissolved in compound 2 among the THF, 6 and 24(500mg)+PTX(214mg) the drippage curtain coating to nylon 12 films, and in 50 ° of C flow baking oven dried overnight.The pig myocardium thin slice is dipped in the pig whole blood.Then place myocardium top to continue to reach 5 minutes nylon 12 films that apply.By in THF, extracting cardiac muscle and carrying out supernatant liquor analysis (with phenyl cyanide as interior mark) by RP-HPLC the PTX of transfer is carried out quantitatively.The PTX that shifts at 30s, 1min and 5min accordingly: compound 2:38.53ng, 209.09ng, 508.94ng; Compound 6:133.23ng, 262.39ng, 1041.07ng; Compound 24:1574.86ng, 3398.16ng, 11890.32ng.
Embodiment 42: the isolated model of PTX dosage when airbag deployment.
Results come from local commercial farm supplier's pig heart and use perfusion of saline.The medicine of effluent gases ductus bursae advances in the position, and this system is unfolded.Mark is carried out in this position, and air bag is extracted out, and this section (sections) is separated fully with cardiac muscle.The analysis of medicament contg relates to the Solid-Phase Extraction (Waters HLB SPE) and the HPLC that organize homogenize, medicine and analyzes.Be retained in medicine on the air bag and be solvent-extracted and analyze by HPLC.
Embodiment 43: after being exposed to blood PTX is held back (reservation) on air bag.
Balloon catheter applies with compound 24+PTX and at room temperature dry 4 days.Then the pig blood that the balloon catheter that applies is exposed to anti-freezing continues 5 minutes.The coating that keeps at balloon catheter with acetonitrile extraction and PTX is carried out quantitatively (the usefulness phenyl cyanide is as interior mark) by RP-HPLC.The %PTX:72.8% that keeps at air bag.
Embodiment 44: launch the release of period P TX in blood.
These balloon catheters apply with compound 24+PTX and at room temperature dry 4 days.Then the pig blood that makes the balloon catheter of these coatings be exposed to anti-freezing continues 4 minutes, then inflation (expansion) and keeping 1 minute.The coating that keeps at balloon catheter with acetonitrile extraction and PTX is carried out quantitatively (the usefulness phenyl cyanide is as interior mark) by RP-HPLC.The %PTX:67.4% that discharges.
Embodiment 45: the zooscopy in rabbit model.
Coating and uncoated air bag are included in this research.In brief, finish carotid ablation.Isolate right common carotid artery, place and advance the 5F intubator, and finish contrast arteria iliacofemoralis angiogram (aortoiliofemoral angiogram) by the 4F angiography catheter that is positioned at the aortic bifurcation top.Intra-arterial injection heparin and lignocaine.Under the fluorescence microscopy guiding, introduce the air bag of coating and uncoated air bag, and inflate according to the research experiment scheme.Based on this research and design, the container outer planting of processing is used for ingestion of medicines is carried out quantitative analysis.Developed and set up for extract drugs and quantitative several different methods.
Embodiment 46: the zooscopy in pig model.
In porcine coronary (male pig Sus scrofa domestica of castrating), the balloon catheter that applies with compound 24 is inflated (expansion) or is placed in inflation (expansion) position, twine, continue to reach 1 minute.Before treatment every day by oral with ASA(0.081g) and clopidogrel (0.075g) gave every animal lasting three days, and before this step overnight fasting.For operation technique, after calmness, marginal ear vein is carried out intubate and be used for intravenous injection inner fluid and medicine.The animal intubate is used for giving anesthetic gases and placing the intubate platform.Under aseptic condition, by the operation cutting-out vascular catheterization device sleeve pipe is placed right carotid artery.Run through this step, keep continuous hemodynamic monitoring and electrocardiogram monitoring.Use guide catheter as calibration reference, to contiguous and away from the blood vessel diameter at the reference site place at implant expection position, and the target site diameter is measured.After this step, the coating that keeps at balloon catheter extracts with acetonitrile and by RP-HPLC PTX is carried out quantitatively (with phenyl cyanide as interior mark).The %PTX that discharges: winding: 60.2; Inflation (expansion): 98.8.
Embodiment 47: the assessment of Inflammatory Mediators (CRP, MCP-1 and IL-6) whole body level.
According to the research experiment scheme, (venipuncture phlebotomy) collects blood in EDTA and the drying tube by the venipuncture venous cutdown.Under 3000rpm with the centrifugal blood in the EDTA pipe 15 minutes and collect blood plasma and be stored under-20 ° of C.To be collected at room temperature that blood in the drying tube remains to that grumeleuse continued 15 minutes and under 3000rpm centrifugal 10 minutes.Then serum is separated and storage.Utilize the immune agglutination effect that serum sample is carried out CRP quantitative.Measure MCP-1 and IL-6 by the ELISA colorimetric method by blood plasma.Be used in the optical density(OD) of measuring under the 450nm wavelength and make the typical curve of MCP-1 and IL-6.Use Student t-check at each time point the result of average CRP, MCP-1 and IL-6 to be carried out statistics relatively.
Embodiment 48: in the assessment of flow condition (blood-circulation model) lower gasbag coating therapeutic reservation.
Send by the tubular junctor of silicone (tubing connection) by the full pig blood pump of peristaltic pump with 37 ° of C anti-freezings.Be similar to blood and by speed coronarius (71.4mL/min) flow rate pump be set.To place the middle part of this blood flow to continue 1 minute with compound 1 or 24 balloon catheters that apply.This coating is measured the PTX that keeps at balloon catheter and carry out quantitatively (using phenyl cyanide as interior mark) with RP-HPLC by peeling off.The %PTX that keeps: compound 1:94.4%, compound 24:52.2%.
Embodiment 49: the assessment of the anti-soil of airbag coatings (antifouling) characteristic.
With compound 1(125mg) be dissolved in THF(1mL) in, and the drippage curtain coating is to nylon film.After in the 500mg/mL of 1mL BSA, hatching 40 minutes, use Xylene Brilliant Cyanine G R dyestuff (CBB) to absorb to nylon film with the nylon film of compound 1 coating for albumen and carry out qualitative assessment.Also negative control (not hatching with BSA) is assessed.With distilled water flushing with after removing the albumen that does not adhere to, add to the 0.25%CBB reagent of 1mL in all samples and hatched 40 minutes.All samples washes with distilled water and is dry.What shown is to compare with the nylon membrane that independent BSA is hatched, and is coated with the nylon membrane that the BSA of compound 1 hatches and shows that lower albumen absorbs (mazarine settling) (Fig. 3).
Embodiment 50: the assessment of medicine shielding effect and adhesive attraction on nylon 12 film sheet.
With compound 1,7 and 14(200mg/mL) be dissolved among the THF.Thereby PTX added to make 25mg/mL solution in each solution.Nylon 12 film sheet are cut into 1 * 1cm size, and on this film sheet, drying is 1 day in 50 ° of C flow baking oven with blend solution drippage curtain coating.Prepare independent PTX and with comparing with same method.PBS pH 7.4 is preheating to 37 ° of C.Under 37 ° of C in substratum (4mL) will test article and the contrast article hatched 10,30,60 and 120 minutes.When each time point finishes, substratum changed and when research finishes, with organic solvent to these films peel off, centrifugal, collect supernatant liquor, and under 60 ° of C, solvent seasoning is spent the night.As interior mark the assessment of medicine shielding effect is analyzed with phenyl cyanide by RP-HPLC.10 minutes PTX discharge (ng/mL) in PBS: compound 1:107.6, compound 7:79.7, compound 14:15.4, independent PTX:651.By NMR oligomeric fluorochemical adhesive power on the film surface is assessed.Produce working curve by NMR for every kind of compound.The coating of peeling off is suspended in CDCl again 3Carry out NMR (1mL).Gone out the quantity of surplus materials by NMR integral area inverse.In PBS, hatch the 120 minutes afterwards per-cent of surplus materials: compound 1:82.1, compound 7:85.5.Carry out the similar assessment of medicine shielding effect at film with the pig whole blood.10 minutes PTX discharge (%) in blood: compound 1:28.8, compound 7:34.0, compound 14:57.4, independent PTX:75.6.
Embodiment 51: the assessment that the therapeutic of airbag coatings keeps in rabbit model
Described in embodiment 42, normally finish angioplasty with the balloon catheter that applies.When reaching therapentic part, balloon catheter shrinks and does not launch.When finishing, research use SEM that the coating integrity is checked.By release coating the PTX concentration that keeps in the coating is measured, and used the following analysis method to carry out quantitatively: high pressure lipuid chromatography (HPLC) (HPLC) and gel permeation chromatography (GPC).
Embodiment 52: oligomeric fluorochemical is as solubilizing agent
With several water-insoluble drugs, compound 24 complexings of taxol (PTX), rapamycin and Ibuprofen BP/EP and 4wt%.Make coating by the drippage casting method at nylon membrane.Also prepared in the same manner the only contrast film of coated medicament.In water, the nylon membrane that applies hatched and be used for measuring drug release in 24 hours.In water, discharge the per-cent of medicine: compound 24+PTX=94, PTX contrast=11, compound 24+ rapamycin=79, rapamycin contrast=4, compound 24+ Ibuprofen BP/EP=80, Ibuprofen BP/EP contrast=40.
Apply these balloon catheters with compound 24+PTX and glycol+PTX of not fluoridizing.Balloon catheter is stripped to the solubleness that is used for being evaluated at aqueous solution floating coat in the water.PTX observed value from release coating in the water is as follows: compound 24+PTX=680 μ g; The glycol of not fluoridizing+PTX=26 μ g.
Embodiment 53: characterize in the lip-deep coating of balloon catheter
Apply balloon catheter according to the experimental program (compound 24+PTX) of setting up.Carry out the coating sign by XPS for the coating air bag of the coating air bag that twines, expansion and the uncoated air bag of winding in contrast.Single carry out Surface Characterization at 4 difference places for each air bag along one.Per-cent at uncoated air bag upper surface fluorine: 0.44,0.26,0.36,0.52; On the air bag that applies (winding): 31.39,30.62,30.71,33.78; On the air bag that applies (expansion): 36.61,32.71,32.93,31.21.Surface Characterization shows that of spreading all over balloon surface is continuous coated.
Embodiment 54: the high PTX on airbag coatings loads
Make compound 1 and 24 and the glycol of nonfluorinated mix with PTX.Apply balloon catheter and drying according to the method for setting up with these solution.Peel off these coatings and measure PTX by HPLC with organic solvent.The PTX observed value is 961 μ g, 713 μ g and 466 μ g accordingly in compound 1, compound 24 and the glycol do not fluoridized.
Embodiment 55: sreen analysis
Apply balloon catheters and at room temperature dry 4 days with compound 24.The balloon catheter that applies is exposed to PBS continues 1 minute, then inflate and kept 1 minute.Use uncoated balloon catheter in contrast.Use HIAC Royco particle collector for particle PBS solution to be analyzed, use USP33-NF28, augment 1,＜789＜788 instruct as general.All samples all passes through the USP＜788〉restriction for SVI(≤100mL).% total differential grain count (5 μ m, 10 μ m, 25 μ m): contrast: 79.8,14.36,0.11; Compound 24:81.2,13.1,0.32.
Embodiment 56: acute general toxicity
To be in the compound 24(12mg/mL among the PBS) the single dose systemic injection give in 5 albino Switzerland Mice Bodies, and in during 72 hours toxicity is observed.Under the injection rate of about 0.1mL/sec, with 50mL/kg mouse is carried out administration.After the injection immediately and the observation of after injection, carrying out mortality ratio and pharmacology and/or toxicological action sign in 4,24,48 and 72 hours.During the research phase, do not observe the clinical indication of toxicity.
Embodiment 57: double-coat
At first with the selection compound nylon 12 films are processed, and then applied with the compound that comprises PTX.PTX discharge to continue 60 minutes (% release) in the tween buffer reagent: compound 1:0.7% individually, compound 11 and compound 1:76%.
Embodiment 58: the assessment of medicine shielding effect and adhesive power on balloon catheter
With compound 1(12.5mg compound 1,50mg PTX, 1mL THF) also or urea preparation (16mg urea, 52mg PTX, 936 μ L THF, 104 μ L water) apply balloon catheter.In PBS, these balloon catheters were hatched 5 minutes.%PTX discharges: compound 1:0.35, urea: 58.02.
Embodiment 59: for the temperature dependency of drug release (PTX discharges under room temperature and 37 ° of C)
Compound 1,6,10 is mixed with 50wt% with PTX.The solution drippage curtain coating that will comprise PTX is on nylon membrane and dry.Under room temperature (RT) and 37 ° of C, in 4mL PBS, these films were hatched 1 minute.Prepare the contrast film of these coatings and peel off in the 4mL organic solvent.Measuring PTX by HPLC discharges.Under room temperature and 37 ° of C, discharge for compound 1,6 and 10 PTX and be accordingly: 4ng and 417ng, 39ng and 543ng and 59ng and 188ng.
Embodiment 60: the solvent-free system of compound 24+PTX
Use different solvents that several compounds is combined with PTX among the embodiment of front.Use these methods that compound 24 is combined with PTX and be combined in the solvent-free system.In 60 ° of C flow baking oven with compound 24(75mg) heat up, add PTX(3mg to) in and mix.At room temperature after 24 hours on a macro scale or microcosmic ground all do not see and be separated.
Other embodiments
All publications, patent and the patent application of mentioning in this manual all is combined in this by reference, and independently ad hoc and individually pointed out to be combined in by reference this by publication or patent application just as each for its degree.
Although describe the present invention in conjunction with its specific embodiments, should be understood that it can further revise, and the application be intended to cover usually follow the principle of the invention and comprise with the known or conventional practice that drops in the field of the present invention relates in this class of disclosing of the present invention of the present invention any change, purposes or the adaptation scheme that depart from, and can be used for essential characteristic proposed above, and in the scope of claims.
Other embodiments within the scope of the claims.

Claims (102)

1. the composition of a formula (XV):
Figure FDA00002022515500011
Wherein
M and n both 0, or m and n both 1;
Each A and A 2To have 50-3, the trifunctional monomer of molecular weight between the 500Da;
Each L and L AJoint independently;
Each R X1A, R X1B, R X2A, and R X2BTo have 200-3 independently, the insoluble segment of the water of molecular weight between the 500Da; And
R Y1To have 100-3, organic segment of the not halogenation of molecular weight between the 500Da; And
As m and n both 1 time, each R Z1And R Z2The insoluble segment of difunctionality water with molecular weight between the 50-3500Da independently; Or
As m and n both 0 time, each R Z1And R Z2To have 200-3 independently, the insoluble segment of the water of molecular weight between the 500Da.
2. composition as claimed in claim 1, wherein said composition is by following formula (XV-A) explanation
Figure FDA00002022515500012
A is the trifunctional monomer with molecular weight between the 50-3500Da;
Each L is joint independently;
R X1And R X2To have 200-3 independently of one another, the Organohalogen compounds segment of molecular weight between the 500Da; And
R Y1To have 100-3, the organic segment of not halogenation of molecular weight between the 500Da.
3. composition as claimed in claim 1, wherein said composition illustrates by following formula (XV-B):
Figure FDA00002022515500021
Wherein
Each A and A 2It is the trifunctional monomer with molecular weight between the 50-3500Da;
Each L and L AJoint independently;
Each R X1A, R X1B, R X2A, and R X2BTo have 200-3 independently of one another, the insoluble segment of the water of molecular weight between the 500Da; And
R Y1To have 100-3, organic segment of the not halogenation of molecular weight between the 500Da; And
Each R Z1The insoluble segment of difunctionality water with molecular weight between the 50-3500Da independently.
4. composition as claimed in claim 3, wherein R Z1It is the glycol of fluoridizing.
5. such as each described composition among the claim 1-4, wherein A comprises triol.
6. such as each described composition among the claim 1-4, wherein A comprises glycerine, TriMethylolPropane(TMP) (TMP), trimethylolethane (TME), trimesic acid (TMA) or three (hydroxyethyl) chlorinated isocyanurates (THEIC).
7. such as each described composition, wherein R among the claim 1-6 Y1Polyoxyethylene glycol, zwitter-ion or the polyvinylpyrrolidone of straight or branched.
8. such as each described composition, wherein R among the claim 1-7 Z1And R Z2Poly-fluorine organic group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BPoly-fluorine organic group independently of one another.
9. such as each described composition, wherein R among the claim 1-7 Z1And R Z2Polysiloxane group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BPolysiloxane group independently of one another.
10. such as each described composition, wherein R among the claim 1-7 Z1And R Z2The polyolefine group independently of one another, or each R wherein X1A, R X1B, R X2A, R X2BThe polyolefine group independently of one another.
11. composition as claimed in claim 1, wherein said composition be by following formula explanation,
Figure FDA00002022515500031
Wherein
F TIt is poly-fluorine organic group;
L is joint;
X 1H, CH 3, or CH 2CH 3
X 2H, CH 3, or CH 2CH 3And
N is from 5 to 50 integer.
12. such as each described composition among the claim 1-11, wherein said joint is that through type (XVI) illustrates:
G 1-(Z 1) o-(Y 1) u-(Z 2) s-(R 10)-(Z 3) t-(Y 2) v-(Z 4) p–G 2 （XVI）
Wherein
G 1It is a key between described poly-fluorine organic group and described joint;
G 2It is a key between described joint and Sauerstoffatom;
Z 1, Z 2, Z 3, and Z 4Be selected from independently of one another O, S and NR 11
R 11Hydrogen or C 1-10Alkyl group;
Y 1And Y 2Be selected from independently of one another carbonyl, thiocarbonyl, alkylsulfonyl or phosphoryl;
O, p, s, t, u and v are 0 or 1 independently of one another; And
R 10To replace or unsubstituted C 1-10Alkyl, have assorted alkyl, the C of 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems of aryl, 3 to 10 atoms ,-(CH 2CH 2O) qCH 2CH 2-wherein q is 1 to 10 integer or with G 1-(Z 1) o-(Y 1) u-(Z 2) s-be connected to-(Z 3) t-(Y 2) v-(Z 4) p-G 2On chemical bond.
13. composition as claimed in claim 1, wherein said composition is that through type (XVII) illustrates:
Figure FDA00002022515500041
Wherein
F TIt is poly-fluorine organic group;
L 2To replace or unsubstituted C 1-10Assorted alkyl, the C of alkyl, 1 to 10 atom 2-10Alkene, C 2-10Alkynes, C 5-10The loop systems of aryl, 3 to 10 atoms ,-(CH 2CH 2O) qCH 2CH 2-, wherein q is 1 to 10 integer;
X 1H, CH 3, or CH 2CH 3
X 2H, CH 3, or CH 2CH 3And
N is from 5 to 50 integer.
14. such as each described composition among claim 8 or the 11-13, wherein said poly-fluorine organic group is to have 100-1, the poly-fluoroalkyl of molecular weight between the 500Da.
15. such as each described composition among claim 8 or the 11-13, wherein said poly-fluorine organic group is general formula CF 3(CF 2) rCH 2CH 2– or CF 3(CF 2) s(CH 2CH 2O) χ-group, wherein r is from 2 to 20 integer, χ is from 1 to 10 integer, and s is from 1 to 20 integer.
16. such as each described composition among claim 8 or the 11-13, wherein said poly-fluorine organic group is general formula CH mF (3-m)(CF 2) rCH 2CH 2-or CH mF (3-m)(CF 2) s(CH 2CH 2O) χ-group, wherein m is 0,1,2 or 3; χ is the integer between 1-10; R is the integer between 2-20; And s is the integer between 1-20.
17. such as each described composition among claim 8 or the 11-13, wherein said poly-fluorine organic group is to be selected from (CF 3) (CF 2) 5CH 2CH 2O-, (CF 3) (CF 2) 7CH 2CH 2O-, (CF 3) (CF 2) 5CH 2CH 2O-, CHF 2(CF 2) 3CH 2O-and (CF 3) (CF 2) 2CH 2O-, 1H, 1H, 2H, 2H-perfluor-1-decanol, 1H, 1H, 2H, 2H-perfluor-1-octanol, 1H, 1H, 5H-perfluor-1-amylalcohol and 1H, 1H, perfluor-n-butyl alcohol and their mixture.
18. a composition comprises following mixture: (i) such as each described composition among the claim 1-17; And (ii) medicine.
19. composition as claimed in claim 18, wherein said medicine is hydrophobic drug.
20. composition as claimed in claim 19, wherein said hydrophobic drug are to be selected from antiproliferative class and rapamycin Macrolide.
21. composition as claimed in claim 20, wherein said hydrophobic drug are to be selected from following antiproliferative: methotrexate, trimetrexate, gemcitabine, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol, Docetaxel, daunorubicin, Dx, gengshengmeisu, idarubicin, bleomycin and tamoxifen.
22. composition as claimed in claim 20, wherein said hydrophobic drug are the rapamycin macrolides that is selected from rapamycin, CCI-779, everolimus and ABT-578.
23. composition as claimed in claim 20, wherein said hydrophobic drug is taxol.
24. such as each described composition, wherein (i) among the claim 18-23: (ii) be the ratio that is in 20:1 to 1:20.
25. such as each described composition among the claim 1-24, further comprise water.
26. composition as claimed in claim 25, wherein said composition is aqueous dispersion.
27. composition as claimed in claim 26, wherein this aqueous dispersion is single-phase or the two-phase dispersion.
28. such as each described composition among the claim 1-24, wherein said composition is solid dispersion.
29. such as each described composition among the claim 1-28, be suitable for systemic injection.
30. such as each described composition among the claim 1-29, with the form of liquid, tablet, capsule, pulvis, injection and suppository.
31. such as each described composition among the claim 1-30, wherein increased the solubleness of hydrophobic drug.
32. the method on the tissue surface that biologically active agent is delivered to mammalian tissues, described method comprises make described surface and comprise (i) oligomeric fluorinated oligomeric thing and (ii) the self-assembled coating of biologically active agent contact, wherein after described contact, do not exist under the medical supply of implantation described self-assembled coating to be positioned on the described tissue surface and with described biologically active agent and be discharged on the described tissue surface.
33. one kind is delivered to the method on the tissue surface in the mammalian tissues with biologically active agent, described method comprises makes described surface contact with the temporary medical supply that is coated with self-assembled coating, described self-assembled coating comprises (i) oligomeric fluorinated oligomeric thing and (ii) biologically active agent, wherein said temporary medical supply, when described contact, described biologically active agent is discharged on the described tissue surface.
34. method as claimed in claim 33, wherein said temporary medical supply can destroy described self-assembled coating, and when described destruction, described biologically active agent is discharged on the described tissue surface.
35. method as claimed in claim 34, wherein said temporary medical supply is deformable temporary medical supply, when being deployed to deformed configuration, described temporary medical supply mechanically destroys described self-assembled coating and described biologically active agent is discharged on the described tissue surface.
36. method as claimed in claim 35, wherein said temporary medical supply are configured to energy source is directed to and are used on the described self-assembled coating in response to described energy to destroy described self-assembled coating.
37. method as claimed in claim 36, wherein said energy are ultrasonic energy, heat energy, electromagnetic energy or vibrational energy.
38. such as each described method among the claim 32-37, wherein by with the described temporary medical supply of described self-assembled coating deposition of solids, spraying, printing or dip-coating described self-assembled coating being applied on the surface of described temporary medical supply.
39. method as claimed in claim 38 wherein is applied to described self-assembled coating on the surface of described equipment with two-step approach; This equipment at first applies with oligomeric fluorinated oligomeric thing, secondly applies with biologically active agent.
40. such as each described method among the claim 32-37, wherein the oligomeric fluorinated oligomeric thing of this self-assembled coating forms the self-assembly layer at described temporary medical supply.
41. such as each described method among the claim 32-37, wherein said coating has from 0.01 to 250 micron thickness.
42. such as each described method among the claim 32-37, wherein from 5% to 55%(w/w) described biologically active agent be delivered to the described mammalian tissues from described temporary medical supply.
43. such as each described method among the claim 32-37, wherein said tissue surface is in blood vessel, described self-assembled coating applies the surface of temporary medical supply, and before being delivered on the described tissue surface, from 25% to 85%(w/w) described biologically active agent be retained on the described medical supply.
44. such as each described method among the claim 32-37, wherein said temporary medical supply self is folding, and when disposing described temporary medical supply from folding configuration to unfolding configuration, from 25% to 85%(w/w) described biologically active agent be retained on the described medical supply.
45. such as each described method among the claim 32-37, wherein said tissue surface is the lumen system of described mammalian tissues.
46. method as claimed in claim 45, wherein said lumen system is blood vessel, vein grafts, synthetic graft, or the tube chamber in respiratory system, urinary system, reproductive system, neural system or the Digestive tract.
47. method as claimed in claim 45, wherein said self-assembled coating is applied on the surface of balloon catheter, be inserted in the lumen system of described mammalian tissues, and the configuration that is deployed to expansion is used for described biologically active agent is transferred on the tissue surface of described lumen system from the described surface of described balloon catheter.
48. such as each described method among the claim 32-37, wherein a kind of component of the oligomeric fluorinated oligomeric thing of this self-assembled coating is absorbable.
49. such as each described method among the claim 32-37, wherein the oligomeric fluorinated oligomeric thing of this self-assembled coating is nonabsorable.
50. such as each described method among the claim 32-37, wherein said self-assembled coating is comprised of the component that has from 1kDa to 60kDa molecular weight.
51. such as each described method among the claim 32-37, wherein said oligomeric fluorinated oligomeric thing has the theoretical molecular from 1kDa to 30kDa.
52. such as each described method among the claim 32-37, wherein said oligomeric fluorinated oligomeric thing comprises a hard segment, a soft chain segment and poly-fluorine organic group, and wherein said oligomeric fluorinated oligomeric thing comprises from 5% to 80%(w/w) described hard segment, from 10% to 90%(w/w) described soft chain segment and from 5% to 80%(w/w) described poly-fluorine organic group.
53. such as each described method among the claim 32-37, wherein spread all over the described self-assembled coating described biologically active agent that distributes equably.
54. such as each described method among the claim 32-37, wherein said self-assembled coating comprises from 1% to 30%(w/w) fluorine atom.
55. such as each described method among the claim 32-37, wherein said self-assembled coating comprises from 0.1% to 50%(w/w) biologically active agent.
56. such as each described method among the claim 32-37, wherein said self-assembled coating comprises from the oligomeric fluorinated oligomeric phase of 20:1 to the 1:20 molar ratio for biologically active agent.
57. such as each described method among the claim 32-37, wherein said self-assembled coating has the glass transition temp of 80 ° of C to 40 ° of C of Cong –.
58. such as each described method among the claim 32-37, wherein said self-assembled coating has from 1.0 to 200g sorptive force.
59. such as each described method among the claim 32-37, wherein said self-assembled coating has from 0.04 to 130cps viscosity.
60. such as each described method among the claim 32-37, wherein said self-assembled coating has the Surface Contact angular lag from 20-120 °.
61. such as each described method among the claim 32-37, wherein the described biologically active agent in described coating has a dissociation constant from 1% to 99% phosphate buffered saline (PBS).
62. such as each described method among the claim 32-61, wherein said biologically active agent is selected from protein, peptide class, carbohydrate, antibiotics, antiproliferative class, rapamycin Macrolide, anodyne class, narcotic class, anti-angiogenic agent class, antithrombotic agent class, vasoactive agent class, antithrombotics class, immunomodulator class, cytotoxic agent class, antiviral agent class, antibody class, neurotransmitter, psychoactive drug class, oligonucleotides, vitamins, lipid and their prodrug.
63. it is vessel wall that method as claimed in claim 62, wherein said biologically active agent are selected from antiproliferative class and rapamycin Macrolide and wherein said tissue surface.
64. such as the described method of claim 63, wherein said biologically active agent is to be selected from following antiproliferative: methotrexate, trimetrexate, gemcitabine, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol, Docetaxel, daunorubicin, Dx, gengshengmeisu, idarubicin, bleomycin and tamoxifen.
65. such as the described method of claim 63, wherein said antiproliferative is taxol.
66. such as the described method of claim 63, wherein said biologically active agent is the rapamycin macrolide that is selected from rapamycin, CCI-779, everolimus and ABT-578.
67. such as each described method among the claim 32-66, wherein said self-assembled coating can be drained.
68. such as each described method among the claim 32-66, wherein said mammalian tissues is in subject.
69. such as each described method among the claim 32-66, wherein said self-assembled coating comprises such as each described composition among the claim 1-31.
70. temporary medical supply with surface that self-assembled coating is deposited thereon, described self-assembled coating comprises (i) oligomeric fluorinated oligomeric thing and (ii) biologically active agent, wherein said temporary medical supply comprises an energy generating element, and described energy generating element can be destroyed described self-assembled coating when activating.
71. such as the described temporary medical supply of claim 70, wherein said energy generating element produces ultrasonic energy, heat energy, electromagnetic energy or vibrational energy.
72. temporary medical supply with surface that self-assembled coating is deposited thereon, described self-assembled coating comprises (i) oligomeric fluorinated oligomeric thing and (ii) biologically active agent, wherein said temporary medical supply is deformable temporary medical supply, when being deployed to deformed configuration, described temporary medical supply mechanically destroys described self-assembled coating.
73. such as the described temporary medical supply of claim 72, the temporary medical cell of wherein said deformable is balloon catheter.
74. such as each described temporary medical supply among the claim 70-73, wherein have from 0.01 to 250 micron thickness at the lip-deep described self-assembled coating of described temporary medical supply.
75. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating is comprised of the component that has from 1kDa to 60kDa molecular weight.
76. such as each described temporary medical supply among the claim 70-73, wherein said oligomeric fluorinated oligomeric thing has the theoretical molecular of 1kDa to 30kDa.
77. such as each described temporary medical supply among the claim 70-73, wherein said oligomeric fluorinated oligomeric thing comprises a hard segment, a soft chain segment and poly-fluorine organic group, wherein said oligomeric fluorinated oligomeric thing comprises from 5% to 80%(w/w) described hard segment, from 10% to 90%(w/w) described soft chain segment and from 5% to 80%(w/w) described poly-fluorine organic group.
78. such as each described temporary medical supply among the claim 70-73, wherein spread all over the described self-assembled coating described biologically active agent that distributes equably.
79. such as each described temporary medical supply among the claim 70-73, wherein by the deposition of solids method described biologically active agent is attached in the described assembling coating.
80. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating comprises from 1% to 30%(w/w) fluorine atom.
81. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating comprises from 0.5% to 50%(w/w) biologically active agent.
82. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating comprises from the oligomeric fluorinated oligomeric phase of 20:1 to the 1:20 molar ratio for biologically active agent.
83. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating has the glass transition temp of 80 ° of C to 40 ° of C of Cong –.
84. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating has from 1.0 to 200g sorptive force.
85. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating has from 0.04 to 130cps viscosity.
86. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating has from 20 °-120 ° Surface Contact angular lag.
87. such as each described temporary medical supply among the claim 70-73, wherein said biologically active agent is selected from protein, peptide class, carbohydrate, antibiotics, antiproliferative class, rapamycin Macrolide, anodyne class, narcotic class, anti-angiogenic agent class, antithrombotic agent class, vasoactive agent class, antithrombotics class, immunomodulator class, cytotoxic agent class, antiviral agent class, antibody class, neurotransmitter, psychoactive drug class, oligonucleotides, vitamins, lipid and their prodrug.
88. such as the described temporary medical supply of claim 87, wherein said biologically active agent is selected from antiproliferative class and rapamycin Macrolide.
89. such as the described temporary medical supply of claim 88, wherein said biologically active agent is to be selected from following antiproliferative: methotrexate, trimetrexate, gemcitabine, vinealeucoblastine(VLB), vincristine(VCR), etoposide, Vumon, topotecan, irinotecan, camptothecine, 9-aminocamptothecin, taxol, Docetaxel, daunorubicin, Dx, gengshengmeisu, idarubicin, bleomycin and tamoxifen.
90. such as the described temporary medical supply of claim 89, wherein said antiproliferative is taxol.
91. such as the described temporary medical supply of claim 88, wherein said biologically active agent is the rapamycin macrolide that is selected from rapamycin, CCI-779, everolimus and ABT-578.
92. such as each described temporary medical supply among the claim 70-73, wherein said self-assembled coating can be drained.
93. such as each described temporary medical supply among the claim 70-92, wherein said self-assembled coating comprises such as each described composition among the claim 1-31.
94. method that is used for biologically active agent is delivered to a position of blood vessel, described method comprises as in the blood vessel as described in each described temporary medical supply is inserted among the claim 70-93, described temporary medical supply is positioned near the described position, and the coating of destroying on described temporary medical supply is delivered to described position with described biologically active agent.
95. method that is used for suppressing a position restenosis of blood vessel, described method comprises in the blood vessel as described in being inserted into such as claim 87 or 88 described temporary medical supplies, and activate described energy generating element, wherein said biologically active agent is selected from antiproliferative class and rapamycin Macrolide.
96. method that is used for suppressing a position restenosis of blood vessel, described method comprises in the blood vessel as described in being inserted into such as claim 87 or 88 described deformable temporary medical supplies, and the temporary medical supply of described deformable is deployed to deformed configuration, and wherein said biologically active agent is selected from antiproliferative class and rapamycin Macrolide.
97. such as each described method among the claim 94-96, wherein said blood vessel is the blood vessel of bifurcated.
98. such as the described method of claim 97, the temporary medical supply of wherein said deformable is catheter air bag.
99. such as the described method of claim 98, further comprise stent deployment at disease location.
100. such as the described method of claim 99, wherein before disposing described catheter air bag, dispose described support.
101. such as the described method of claim 99, wherein after disposing described catheter air bag, dispose described support.
102. such as the described method of claim 99, wherein dispose described catheter air bag and be used for the treatment of in-stent restenosis.
CN2010800640811A 2009-12-18 2010-12-20 Local delivery of drugs from self assembled coatings Pending CN102933658A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US28786209P 2009-12-18 2009-12-18
US61/287,862 2009-12-18
PCT/CA2010/002036 WO2011072398A1 (en) 2009-12-18 2010-12-20 Local delivery of drugs from self assembled coatings

Publications (1)

Publication Number Publication Date
CN102933658A true CN102933658A (en) 2013-02-13

Family

ID=44166690

Family Applications (1)

Application Number Title Priority Date Filing Date
CN2010800640811A Pending CN102933658A (en) 2009-12-18 2010-12-20 Local delivery of drugs from self assembled coatings

Country Status (6)

Country Link
US (4) US8900603B2 (en)
EP (1) EP2513225A4 (en)
JP (1) JP2013514278A (en)
CN (1) CN102933658A (en)
CA (2) CA2784689A1 (en)
WO (1) WO2011072398A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106132469A (en) * 2014-04-01 2016-11-16 泰尔茂株式会社 Sacculus coating method
CN106163603A (en) * 2014-04-01 2016-11-23 泰尔茂株式会社 Localization method for sacculus coating
CN107335127A (en) * 2016-04-28 2017-11-10 美敦力心血管股份有限公司 The method of medical treatment device and the balloon-expandable for covering medical treatment device
CN107847344A (en) * 2015-05-21 2018-03-27 网关设备有限公司 Vein access device
CN110891621A (en) * 2017-05-30 2020-03-17 赢创加拿大公司 Vascular graft with modified surface
CN111839648A (en) * 2020-09-02 2020-10-30 青岛市市北区蓝天心理研究所 Uterus hemostasis device of gynaecology

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2203498B1 (en) 2007-10-05 2017-12-06 Interface Biologics Inc. Oligofluorinated cross-linked polymers and uses thereof
WO2010025398A1 (en) 2008-08-28 2010-03-04 Interface Biologics Inc. Thermally stable biuret and isocyanurate based surface modifying macromolecules and uses thereof
CA2716502C (en) 2009-05-15 2015-06-16 Interface Biologics, Inc. Antithrombogenic hollow fiber membranes and filters
CA2784689A1 (en) 2009-12-18 2011-06-23 Interface Biologics, Inc. Local delivery of drugs from self assembled coatings
ITRM20110687A1 (en) * 2011-12-27 2013-06-28 Vincenzo Quaranta CONTROLLED DRUG RELEASE DEVICE.
US9872940B2 (en) 2013-04-01 2018-01-23 Terumo Kabushiki Kaisha Drug coating layer
US11839698B2 (en) 2014-03-13 2023-12-12 W. L. Gore & Associates, Inc. Drug composition and coating
CN106132470B (en) 2014-04-01 2019-09-24 泰尔茂株式会社 Localization method for sacculus coating
JP6866156B2 (en) 2014-04-01 2021-04-28 テルモ株式会社 Balloon coating method, coat layer control method and balloon coating device
US10143779B2 (en) 2014-05-16 2018-12-04 Terumo Kabushiki Kaisha Method of inhibiting thickening of vascular intima
US10188771B2 (en) 2014-05-16 2019-01-29 Terumo Kabushiki Kaisha Method of treating peripheral artery diseases in lower limbs
US10149925B2 (en) 2014-05-16 2018-12-11 Terumo Kabushiki Kaisha Method of reducing the risk of embolization of peripheral blood vessels
WO2016054733A1 (en) 2014-10-06 2016-04-14 Interface Biologics, Inc. Packaging materials including a barrier film
US10975197B2 (en) * 2014-12-16 2021-04-13 Evonik Canada Inc. Ester-linked surface modifying macromolecules
US10441757B2 (en) 2015-01-22 2019-10-15 Intersect Ent, Inc. Drug-coated balloon
JP6723807B2 (en) 2015-04-23 2020-07-15 テルモ株式会社 Balloon coating method, balloon rotation method and balloon coating apparatus
US10561766B2 (en) 2015-09-15 2020-02-18 W. L. Gore & Associates, Inc. Drug composition and coating
US20180311482A1 (en) * 2015-10-30 2018-11-01 Acotec Scientific Co. Ltd. Drug coated balloon catheter arteriovenous shunt
DK3455269T3 (en) * 2016-05-10 2023-12-18 Evonik Canada Inc IMPLANTABLE GLUCOSE SENSORS WITH A BIOSTABLE SURFACE
EP3529300A4 (en) 2016-10-18 2020-03-18 Evonik Canada Inc. Plasticized pvc admixtures with surface modifying macromolecules and articles made therefrom
EP3641730B1 (en) 2017-06-22 2021-03-03 SNBioscience Inc. Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same
CN110891997B (en) 2017-07-14 2022-05-24 费森尤斯医疗保健控股公司 Method for providing surface modification compositions with improved byproduct removal
GB2571696B (en) 2017-10-09 2020-05-27 Compass Pathways Ltd Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced
BR112020018358A2 (en) * 2018-03-09 2020-12-29 Evonik Canada Inc. CARBONATE BOUND SURFACE MODIFIER MACROMOLECULES
CN112638436A (en) * 2018-05-22 2021-04-09 界面生物公司 Compositions and methods for drug delivery to vessel walls
US10688289B2 (en) 2018-06-12 2020-06-23 Intersect Ent, Inc. Systems and methods for sinus access
US11672959B2 (en) 2019-01-18 2023-06-13 Intersect Ent, Inc. Expandable member systems and methods for drug delivery
EP3919093A4 (en) * 2019-02-27 2022-03-30 TERUMO Kabushiki Kaisha Medical instrument manufacturing method and medical instrument
KR20220008824A (en) 2019-04-17 2022-01-21 컴퍼스 패쓰파인더 리미티드 How to treat anxiety disorders, headache disorders and eating disorders with psilocybin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098477A2 (en) * 2001-06-07 2002-12-12 Santerre Paul J Bioactive surface modifiers for polymers and articles made therefrom
CN101203250A (en) * 2005-04-15 2008-06-18 界面生物公司 Methods and compositions for the delivery of biologically active agents
WO2009043174A1 (en) * 2007-10-05 2009-04-09 Interface Biologics Inc. Oligofluorinated cross-linked polymers and uses thereof
WO2009049426A1 (en) * 2007-10-19 2009-04-23 Interface Biologics Inc. Self-eliminating coatings
WO2009129385A1 (en) * 2008-04-16 2009-10-22 Abbott Laboratories Cationic lipids and uses thereof

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3929922A (en) 1965-09-29 1975-12-30 Studiengesellschaft Kohle Mbh Novel large ring compounds
US5674192A (en) 1990-12-28 1997-10-07 Boston Scientific Corporation Drug delivery
GB9221220D0 (en) 1992-10-09 1992-11-25 Sandoz Ag Organic componds
EP1632259B1 (en) 1993-07-19 2011-12-21 Angiotech Pharmaceuticals, Inc. Anti-angiogene compositions and methods of use
US5362718A (en) 1994-04-18 1994-11-08 American Home Products Corporation Rapamycin hydroxyesters
US6774278B1 (en) 1995-06-07 2004-08-10 Cook Incorporated Coated implantable medical device
CA2228505C (en) 1995-08-03 2007-11-06 Paul J. Santerre Fluoroligomer surface modifiers for polymers and articles made therefrom
US6515016B2 (en) 1996-12-02 2003-02-04 Angiotech Pharmaceuticals, Inc. Composition and methods of paclitaxel for treating psoriasis
US5868719A (en) * 1997-01-15 1999-02-09 Boston Scientific Corporation Drug delivery balloon catheter device
EP2292225B9 (en) 1997-03-31 2012-06-27 Boston Scientific Scimed Limited Dosage form comprising taxol in crystalline form
US20030199425A1 (en) 1997-06-27 2003-10-23 Desai Neil P. Compositions and methods for treatment of hyperplasia
US6306166B1 (en) 1997-08-13 2001-10-23 Scimed Life Systems, Inc. Loading and release of water-insoluble drugs
US6890546B2 (en) 1998-09-24 2005-05-10 Abbott Laboratories Medical devices containing rapamycin analogs
US8177743B2 (en) 1998-05-18 2012-05-15 Boston Scientific Scimed, Inc. Localized delivery of drug agents
US6206283B1 (en) 1998-12-23 2001-03-27 At&T Corp. Method and apparatus for transferring money via a telephone call
US6280411B1 (en) 1998-05-18 2001-08-28 Scimed Life Systems, Inc. Localized delivery of drug agents
ATE211931T1 (en) 1998-06-26 2002-02-15 Quanam Medical Corp TOPOISOMERASE INHIBITORS FOR RESTENOSE PREVENTION
US6506408B1 (en) 2000-07-13 2003-01-14 Scimed Life Systems, Inc. Implantable or insertable therapeutic agent delivery device
AU2001293161B2 (en) * 2000-09-29 2005-03-24 Ethicon, Inc. Coatings for medical devices
WO2002062335A2 (en) 2001-01-16 2002-08-15 Vascular Therapies, Llc Implantable device containing resorbable matrix material and anti-proliferative drugs for preventing or treating failure of hemodialysis vascular access and other vascular grafts
DE10115740A1 (en) 2001-03-26 2002-10-02 Ulrich Speck Preparation for restenosis prophylaxis
JP2005514438A (en) 2001-12-21 2005-05-19 ソーン， デイビッド エス． Use of oligomers and polymers for solubilization, stabilization and delivery of drugs
US7470281B2 (en) 2002-04-26 2008-12-30 Medtronic Vascular, Inc. Coated stent with crimpable coating
BR0310008A (en) 2002-05-09 2005-02-15 Hemoteq Gmbh Preparation, method and use of hemocompatible coatings for the prevention of restenosis
ATE495769T1 (en) 2002-07-12 2011-02-15 Cook Inc COATED MEDICAL DEVICE
DE10244847A1 (en) 2002-09-20 2004-04-01 Ulrich Prof. Dr. Speck Medical device for drug delivery
JP4791349B2 (en) 2003-02-28 2011-10-12 バイオインターラクションズ リミテッド Polymer network system for medical devices and method of use
US7226473B2 (en) * 2003-05-23 2007-06-05 Brar Balbir S Treatment of stenotic regions
JP2007505658A (en) 2003-09-15 2007-03-15 アトリウム メディカル コーポレーション Application of therapeutic substances to tissue sites using expandable medical devices
US7476246B2 (en) 2003-12-12 2009-01-13 C. R. Bard, Inc. Implantable medical devices with fluorinated polymer coatings, and methods of coating thereof
EP1753476B1 (en) 2004-03-10 2015-07-29 OrbusNeich Medical, Inc. Progenitor endothelial cell capturing with a drug eluting implantable medical device
JP4949227B2 (en) 2004-03-19 2012-06-06 アボット・ラボラトリーズ Multidrug delivery from balloons and prostheses
US8431145B2 (en) 2004-03-19 2013-04-30 Abbott Laboratories Multiple drug delivery from a balloon and a prosthesis
US9000040B2 (en) 2004-09-28 2015-04-07 Atrium Medical Corporation Cross-linked fatty acid-based biomaterials
US8241656B2 (en) 2005-09-21 2012-08-14 Surmodics, Inc Articles including natural biodegradable polysaccharides and uses thereof
US8021678B2 (en) 2006-02-10 2011-09-20 Advanced Cardiovascular Systems, Inc. Implantable medical device with polymer coating in a surface area to volume ratio providing surface erosion characteristics
WO2007148230A2 (en) * 2006-04-14 2007-12-27 Interface Biologics Incorporated Grafted polymers and uses thereof
US7727541B2 (en) 2006-05-18 2010-06-01 Boston Scientific Scimed, Inc. Medical devices having polymeric regions based on vinyl ether block copolymers
WO2008003298A2 (en) 2006-07-03 2008-01-10 Hemoteq Ag Manufacture, method, and use of active substance-releasing medical products for permanently keeping blood vessels open
US9028859B2 (en) 2006-07-07 2015-05-12 Advanced Cardiovascular Systems, Inc. Phase-separated block copolymer coatings for implantable medical devices
US8153181B2 (en) 2006-11-14 2012-04-10 Boston Scientific Scimed, Inc. Medical devices and related methods
US8425459B2 (en) 2006-11-20 2013-04-23 Lutonix, Inc. Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent
EP2102258B1 (en) 2006-12-14 2016-10-19 Interface Biologics Inc. Surface modifying macromolecules with high degradation temperatures and uses thereof
US20080146489A1 (en) 2006-12-15 2008-06-19 Pacetti Stephen D Regional delivery of therapeutic agents for the treatment of vascular diseases
US7767726B2 (en) 2007-05-11 2010-08-03 Boston Scientific Scimed, Inc. Medical devices having crosslinked polymeric surfaces
US9248219B2 (en) 2007-09-14 2016-02-02 Boston Scientific Scimed, Inc. Medical devices having bioerodable layers for the release of therapeutic agents
WO2009135125A2 (en) 2008-05-01 2009-11-05 Bayer Schering Pharma Ag Catheter balloon drug adherence techniques and methods
WO2010025398A1 (en) 2008-08-28 2010-03-04 Interface Biologics Inc. Thermally stable biuret and isocyanurate based surface modifying macromolecules and uses thereof
IT1394522B1 (en) 2009-01-09 2012-07-05 Invatec Technology Ct Gmbh MEDICAL DEVICE WITH DRUG RELEASE
US20100239635A1 (en) 2009-03-23 2010-09-23 Micell Technologies, Inc. Drug delivery medical device
CN105214143A (en) 2009-04-28 2016-01-06 苏尔莫迪克斯公司 For sending the apparatus and method of bioactivator
EP2248541B1 (en) 2009-05-07 2018-10-31 Biotronik Ag Medication-coated balloon catheter and method for manufacturing the same
US8951595B2 (en) 2009-12-11 2015-02-10 Abbott Cardiovascular Systems Inc. Coatings with tunable molecular architecture for drug-coated balloon
CA2784689A1 (en) * 2009-12-18 2011-06-23 Interface Biologics, Inc. Local delivery of drugs from self assembled coatings
DE102010022588A1 (en) 2010-05-27 2011-12-01 Hemoteq Ag Balloon catheter with a particle-free drug-releasing coating
EP2588157B1 (en) 2010-06-30 2020-03-18 SurModics, Inc. Lipid coating for medical devices delivering bioactive agent
US9757497B2 (en) 2011-05-20 2017-09-12 Surmodics, Inc. Delivery of coated hydrophobic active agent particles
US9861727B2 (en) 2011-05-20 2018-01-09 Surmodics, Inc. Delivery of hydrophobic active agent particles
US10213529B2 (en) 2011-05-20 2019-02-26 Surmodics, Inc. Delivery of coated hydrophobic active agent particles
CA2841360A1 (en) 2011-07-15 2013-01-24 Micell Technologies, Inc. Drug delivery medical device
US10188772B2 (en) 2011-10-18 2019-01-29 Micell Technologies, Inc. Drug delivery medical device
US9956385B2 (en) 2012-06-28 2018-05-01 The Spectranetics Corporation Post-processing of a medical device to control morphology and mechanical properties
WO2014011805A1 (en) 2012-07-10 2014-01-16 Bayer Pharma Aktiengesellschaft Catheter with drug coating
CN104623740B (en) 2013-11-15 2018-02-16 微创心脉医疗科技（上海）有限公司 A kind of medicinal balloon and preparation method thereof
US10525171B2 (en) 2014-01-24 2020-01-07 The Spectranetics Corporation Coatings for medical devices

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098477A2 (en) * 2001-06-07 2002-12-12 Santerre Paul J Bioactive surface modifiers for polymers and articles made therefrom
CN101203250A (en) * 2005-04-15 2008-06-18 界面生物公司 Methods and compositions for the delivery of biologically active agents
WO2009043174A1 (en) * 2007-10-05 2009-04-09 Interface Biologics Inc. Oligofluorinated cross-linked polymers and uses thereof
WO2009049426A1 (en) * 2007-10-19 2009-04-23 Interface Biologics Inc. Self-eliminating coatings
WO2009129385A1 (en) * 2008-04-16 2009-10-22 Abbott Laboratories Cationic lipids and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MOHAMED ALLOUCH ET AL: "Nonionic amphiphilic compounds from aspartic and glutamic acid sa structural mimics of lecithins", 《JOURNAL OF THE AMERICAN OIL CHEMISTS’SOCIETY》 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106132469A (en) * 2014-04-01 2016-11-16 泰尔茂株式会社 Sacculus coating method
CN106163603A (en) * 2014-04-01 2016-11-23 泰尔茂株式会社 Localization method for sacculus coating
CN106163603B (en) * 2014-04-01 2019-11-15 泰尔茂株式会社 Localization method for sacculus coating
CN106132469B (en) * 2014-04-01 2019-11-15 泰尔茂株式会社 Sacculus coating method
CN107847344A (en) * 2015-05-21 2018-03-27 网关设备有限公司 Vein access device
CN107847344B (en) * 2015-05-21 2021-10-01 网关设备有限公司 Venous access device
CN107335127A (en) * 2016-04-28 2017-11-10 美敦力心血管股份有限公司 The method of medical treatment device and the balloon-expandable for covering medical treatment device
CN107335127B (en) * 2016-04-28 2022-04-12 美敦力心血管股份有限公司 Medical device and method for covering an inflatable balloon of a medical device
CN110891621A (en) * 2017-05-30 2020-03-17 赢创加拿大公司 Vascular graft with modified surface
CN110891621B (en) * 2017-05-30 2022-07-08 赢创加拿大公司 Vascular graft with modified surface
CN111839648A (en) * 2020-09-02 2020-10-30 青岛市市北区蓝天心理研究所 Uterus hemostasis device of gynaecology

Also Published As

Publication number Publication date
US20150283304A1 (en) 2015-10-08
WO2011072398A1 (en) 2011-06-23
US20220040385A1 (en) 2022-02-10
EP2513225A1 (en) 2012-10-24
JP2013514278A (en) 2013-04-25
US20190298889A1 (en) 2019-10-03
EP2513225A4 (en) 2015-08-12
US8900603B2 (en) 2014-12-02
CA3037168A1 (en) 2011-06-23
US20130142834A1 (en) 2013-06-06
CA2784689A1 (en) 2011-06-23
US10195311B2 (en) 2019-02-05

Similar Documents

Publication Publication Date Title
CN102933658A (en) Local delivery of drugs from self assembled coatings
US8445016B2 (en) Grafted polymers and uses thereof
US10039864B2 (en) Oligofluorinated cross-linked polymers and uses thereof
CA2604696C (en) Polymer-biologically active agent complexes for localized delivery of said biologically active agent
US20220047773A1 (en) Self-eliminating coatings
JP5214141B2 (en) Bioactive block copolymer
ES2764400T3 (en) Multifunctional implant surface coating
CN102091355A (en) Compound coating coronary medicament eluting stent and preparation method thereof
ES2707527T3 (en) Manufacturing process of an adaptable medical device and device obtained by said process
JP5148106B2 (en) Photoactive biocompatible coating composition
JP2007512419A (en) Biocompatible polymerization accelerator

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1182123

Country of ref document: HK

C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20130213